Novel heterocycles

ABSTRACT

Described are novel heterocyclic compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof. These compounds are useful in the treatment of immunological diseases, inflammation, pain disorder, rheumatoid arthritis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; atherosclerosis; cancer; cachexia; ischemic-induced cell damage; pancreatic beta cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; ARDS; psoriasis; Crohn&#39;s disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; muscle degeneration; asthma; COPD; bone resorption diseases; multiple sclerosis; sepsis; septic shock; toxic shock syndrome and fever. More particularly these compounds are useful as PDE4 inhibitors and are useful for treating PDE4 mediated diseases.

FIELD

Described are novel heterocyclic compounds of the general formula (I),their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs,hydrates, solvates, pharmaceutically acceptable salts and compositions,metabolites and prodrugs thereof.

The present invention also relates to a process for the preparation ofthe above said novel heterocyclic compounds of the general formula (I).

The novel heterocyclic compounds of the present invention are useful forthe treatment of inflammation and immunological diseases. Particularlythe compounds of the present invention are useful for the treatment ofcancer, inflammation and immunological diseases those mediated bycytokines such as TNF-α, IL-1, IL-6, IL-1β, IL-8, IL-12 andcyclooxygenases such as COX-1, COX-2 and COX-3. More particularly, thecompounds of the present invention are useful as PDE4 inhibitors, andare useful for treating PDE4 mediated diseases such as asthma, COPD,IBD, arthritis, psoriasis and the like. They are also useful for thetreatment of rheumatoid arthritis; osteoporosis; multiple myeloma;uveititis; acute and chronic myelogenous leukemia; ischemic heartdisease, atherosclerosis, cancer, ischemic-induced cell damage,pancreatic β cell destruction; osteoarthritis; rheumatoid spondylitis;gouty arthritis; IBD; adult respiratory distress syndrome (ARDS);psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis;anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia;type I and type II diabetes; bone resorption diseases; ischemiareperfusion injury; brain trauma; multiple sclerosis; cerebral malaria;sepsis; septic shock; toxic shock syndrome; fever; myalgias due toinfection and diseases mediated by HIV-1; HIV-2; HIV-3; cytomegalovirus(CMV); influenza; adenovirus; the herpes viruses (including HSV-1,HSV-2) and herpes zoster viruses.

BACKGROUND

The present invention is concerned with the treatment of immunologicaldiseases or inflammation, notably such diseases are mediated bycytokines or cyclooxygenases. The principal elements of the immunesystem are macrophages or antigen-presenting cells, T cells and B cells.The role of other immune cells such as NK cells, basophils, mast cellsand dendritic cells are known, but their role in primary immunologicdisorders is uncertain. Macrophages are important mediators of bothinflammation and provide the necessary “help” for T cell stimulation andproliferation. Most importantly macrophages make IL-1, IL-12 and TNF-α,all of which are potent pro-inflammatory molecules and also provide helpfor T cells. In addition, activation of macrophages results in theinduction of enzymes, such as cyclooxygenase-2 (COX-2) andcyclooxygenase-3 (COX-3), inducible nitric oxide synthase (iNOS) andproduction of free radicals capable of damaging normal cells. Manyfactors activate macrophages, including bacterial products,superantigens and interferon gamma (IFN γ). It is believed thatphosphotyrosine kinases (PTKs) and other undefined cellular kinases areinvolved in the activation process.

Cytokines are molecules secreted by the immune cells, large number ofchronic and acute conditions have been recognized to be associated withperturbation of the inflammatory responses. A large number of cytokinesparticipate in this response, including IL-1, IL-6, IL-8 and TNF. Itappears that the activity of these cytokines in the regulation ofinflammation relies at least in part on the activation of an enzyme onthe cell-signaling pathway, a member of the MAP known as CSBP and RK.This kinase is activated by dual phosphorylation after stimulation byphysiochemical stress, treatment with lipopolysaccharides or withproinflammatory cytokines such as IL-1 and TNF. Therefore, inhibitors ofthe kinase activity of p38 are useful anti-inflammatory agents.

Cytokines are molecules secreted by the immune cells that are importantin mediating immune responses. Cytokine production may lead to thesecretion of other cytokines, altered cellular function, cell divisionor differentiation. Inflammation is the normal response of the body toinjury or infection. However, in inflammatory diseases such asrheumatoid arthritis, pathologic inflammatory processes can lead tomorbidity and mortality. The cytokine tumor necrosis factor-alpha(INF-α) plays a central role in the inflammatory response and has beentargeted as a point of intervention in inflammatory diseases. TNF-α is apolypeptide hormone released by activated macrophages and other cells.At low concentrations, TNF-α participates in the protective inflammatoryresponse by activating leukocytes and promoting their migration toextravascular sites of inflammation (Moser et al., J Clin Invest, 83,444-55, 1989). At higher concentrations, TNF-α can act as a potentpyrogen and induce the production of other pro-inflammatory cytokines(Haworth et al., Eur J Immunol, 21, 2575-79, 1991; Brennan et al.,Lancet, 2, 244-7, 1989). TNF-α also stimulates the synthesis ofacute-phase proteins. In rheumatoid arthritis, a chronic and progressiveinflammatory disease affecting about 1% of the adult U.S. population,TNF-α mediates the cytokine cascade that leads to joint damage anddestruction (Arend et al., Arthritis Rheum, 38, 151-60, 1995).Inhibitors of TNF-α, including soluble TNF receptors, Etanercept(Goldenberg, Clin Ther, 21, 75-87, 1999 and anti-TNF-α antibody) andInfliximab (Luong et al., Ann Pharmacother, 34, 743-60, 2000), arerecently approved by the U.S. FDA for the treatment of rheumatoidarthritis.

Elevated levels of TNF-α have also been implicated in many otherdisorders and disease conditions, including cachexia, septic shocksyndrome, osteoarthritis, inflammatory bowel disease (IBD) such asCrohn's disease and ulcerative colitis etc.

Elevated levels of TNF-α and/or IL-1 over basal levels have beenimplicated in mediating or exacerbating a number of disease statesincluding rheumatoid arthritis; osteoporosis; multiple myeloma;uveititis; acute and chronic myelogenous leukemia; pancreatic β celldestruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis;inflammatory bowel disease; adult respiratory distress syndrome (ARDS);psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis;anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia;type I and type II diabetes; bone resorption diseases; ischemiareperfusion injury; atherosclerosis; brain trauma; multiple sclerosis;cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, andmyalgias due to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV),influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), andherpes zoster are also exacerbated by TNF-α.

It can be seen that inhibitors of TNF-α are potentially useful in thetreatment of a wide variety of diseases. Compounds that inhibit TNF-αhave been described in several patents.

Cytokines play an important role in the communication between cells ofmulticellular organisms. Early studies indicate that B cells lineagetend to secrete IL-6 in response to host immune defense mechanisms, butin recent decades studies have indicated elevated levels of IL-6 invarious cancer phenotypes.

IL-6 has been found to be a growth factor for multiple myeloma cells;anti IL-6 antibodies were shown to block myeloma cell proliferation inleukemic patients Lkein et al., Blood, 78, 5, 1198-1204, 1991 and Lu etal., Eur. J. Immunol., 22. 2819-24, 1992.

Elevation of inflammatory cytokine levels, particularly IL-6 and TNF-αalso appears to be associated with the cancer-related cachexia, asyndrome involving loss of adipose and skeletal muscle tissue and onethat is not responsive to increased caloric intake. Cachexia may also berelated to the role of acute phase proteins. The acute phase responseand production of acute phase proteins e.g., C-reactive protein (CRP)are mediated by IL-6. Studies correlate elevated levels of IL-6 toelevated acute phase proteins, which interestingly are also associatedwith increased weight loss and decreased survival. Thus, with elevatedIL-6 levels, amino acid metabolism is directed away from peripheraltissues to the liver for production of acute phase proteins, this inturn leads to muscle wasting, which is a component of cachexia.Accordingly, the cytokine-induced acute phase response may be a primarycomponent of cancer-related cachexia. Moreover, diminishing or blockingIL-6 activity in animal models attenuates cachexia, furtherdemonstrating the essential role IL-6 plays in the development of thissyndrome.

Thus, having a compound with IL-6 inhibitory activity may be useful forvarious inflammatory diseases, sepsis, multiple myeloma, plasmacytoidleukemia, osteoporosis, cachexia, psoriasis, Nephritis, Kaposi'ssarcoma, rheumatoid arthritis autoimmune disease, endometriosis andsolid cancer (WO02/074298 A1). Compounds that inhibit IL-6 have beendescribed in U.S. Pat. No. 6,004,813; U.S. Pat. No. 5,527,546 and U.S.Pat. No. 5,166,137.

The cytokine IL-1β also participates in the inflammatory response. Itstimulates thymocyte proliferation, fibroblast growth factor activityand the release of prostaglandins from synovial cells. Elevated orunregulated levels of the cytokine IL-1β have been associated with anumber of inflammatory diseases and other disease states, including butnot limited to adult respiratory distress syndrome, allergy, Alzheimer'sdisease etc. Since overproduction of IL-1β is associated with numerousdisease conditions, it is desirable to develop compounds that inhibitthe production or activity of IL-1β.

In rheumatoid arthritis models in animals, multiple intra-articularinjections of IL-1 have led to an acute and destructive form ofarthritis (Chandrasekhar et al., Clinical Immunol Immunopathol. 55, 382,1990). In studies using cultured rheumatoid synovial cells, IL-1 is amore potent inducer of stromelysin than TNF-α. (Firestein, Am. J.Pathol. 140, 1309, 1992). At sites of local injection, neutrophil,lymphocyte and monocyte emigration has been observed. The emigration isattributed to the induction of chemokines (e.g., IL-8) and theup-regulation of adhesion molecules (Dinarello, Eur. Cytokine Netw. 5,517-531, 1994).

In rheumatoid arthritis, both IL-1 and TNF-α induce synoviocytes andchondrocytes to produce collagenase and neutral proteases, which leadsto tissue destruction within the arthritic joints. In a model ofarthritis (collagen-induced arthritis, CIA in rats and mice)intra-articular administration of TNF-α either prior to or after theinduction of CIA led to an accelerated onset of arthritis and a moresevere course of the disease (Brahn et al., Lymphokine Cytokine Res. 11,253, 1992; and Cooper, Clin. Exp. Immunol. 898, 244, 1992).

IL-8 has been implicated in exacerbating and/or causing many diseasestates in which massive neutrophil infiltration into sites ofinflammation or injury (e.g., ischemia) is mediated; chemotactic natureof IL-8, including, but is not limited to, the following: asthma,inflammatory bowel disease, psoriasis, adult respiratory distresssyndrome, cardiac and renal reperfusion injury, thrombosis andglomerulonephritis. In addition to the chemotaxis effect on neutrophils,IL-8 also has ability to activate neutrophils. Thus, reduction in IL-8levels may lead to diminish neutrophil infiltration.

IL-12 is a heterodimeric cytokine. Consisting of a p40 and a p35 subunitwith potent immunoregulatory properties, primarily released byantigen-presenting cells, dendritic cells and monocytes/macrophages inresponse to bacterial product and immune signals. It enhances naturalkiller (NK)-mediated cytotoxicity and induces interferon-gamma (IFN-g)production by NK cells and T lymphocytes. IL-12 plays a key role inpromoting Th1 immune responses, as demonstrated both in vitro and invivo. Accordingly, antibodies against IL-12 have been used to beneficialeffect in experimental models for auto immune diseases that areTh1-driven, such as experimental allergic encephalomyelitis (EAE) and2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced chronic intestinalinflammation in mice, a model for human inflammatory bowel disease. InTNBS treated mice, administration of anti-IL-12 after induction ofcolitis let to a striking improvement of established disease, clinicallyand histo-pathologically, associated with a decrease in IFN-g productionby ex vivo stimulated lamina propria CD4+ cells. Similarly, anti-IL-12treatment in C3H mice infected with Borrelia burgorferi significantlyreduced the severity of Lyme arthritis, accompanied by a decrease inIFN-g serum levels. Several lines of evidence support the critical roleof IL-12 in the pathogenesis of CD, including IL-12 expression bymononuclear cells also increased in CD patients versus controls (KakazuT et al. Am J Gastroenterol. 1999, 94, 2149-2155).

IL-12 production was increased in surgical specimens from CD patientscompared with specimens from control patients with cecum cancer(Colpaert S et al. Eur Cytokine Netw. 2002, 13, 431-437). Many clustersof IL-12-positive cells were found in pediatric CD ileal specimens andgastric mucosa, compared with few or no clusters in H. pylori gastritisspecimens and normal gastric mucosa (Berrebi D et al. Am J Pathol. 1998,152, 667-672). Substantial proportions of IL-12-containing macrophageswere present in the intestinal lamina propria and muscularis propria inactive CD, whereas these cells were rarely detected or were undetectablein controls with non-inflammatory gut disorders (Parronchi P et al. Am.J. Pathol. 1997, 150, 823-832). IL-12 p40 mRNA was detected in laminapropria mononuclear cells isolated from 11/13 patients with CD comparedwith 1/13 healthy controls (P<0.001) (Monteleone G et al.Gastroenterology. 1997, 112, 1169-1178). IL-12 mRNA expression wassignificantly increased in colonic biopsy specimens from patients withactive CD compared with healthy controls (P<0.04) (Nielsen O H et al.Scand. J. Gastroenterol. 2003, 38, 180-185)

It has been reported that the cyclooxygenase enzyme exists in threeisoforms, namely, COX-1, COX-2 and COX-3. COX-1 enzyme is essential andprimarily responsible for the regulation of gastric fluids whereas COX-2enzyme is present at the basal levels and is reported to have a majorrole in the prostaglandin synthesis for inflammatory response. Theseprostaglandins are known to cause inflammation in the body; hence, ifthe synthesis of these prostaglandins is stopped by way of inhibitingCOX-2 enzyme, inflammation and its related disorders can be treated.COX-3 possesses glycosylation-dependent cyclooxygenase activity.Comparison of canine COX-3 activity with murine COX-1 and COX-2demonstrated that this enzyme is selectively inhibited byanalgesic/antipyretic drugs such as acetaminophen, phenacetin,antipyrine and dipyrone and is potently inhibited by some nonsteroidalanti-inflammatory drugs. Thus, inhibition of COX-3 could represent aprimary central mechanism by which these drugs decrease pain andpossibly fever. Earlier reports prior to Coxib's development show thatinhibitors of COX-1 enzyme causes gastric ulcers, whereas selectiveCOX-2 and COX-3 enzyme inhibitors are devoid of this function and henceare found to be safe. But, recent reports show that the selective COX-2inhibitors (COXIB's) are associated with cardiovascular risks. So,inhibition of COX-2 without causing cardiovascular risks and gastriculcers due to inhibition of COX-1 are shown to be safe.

Phosphodiesterases (“PDE”) are a family of enzymes that metabolize 3′5′cyclic nucleotides to 5′ nucleoside monophosphates thereby terminatingcamp second messenger activity. A particular phosphodiesterase,phosphodiesterase-4 (“PDE4” also known as “PDE IV”), which is a highaffinity, cAMP specific, type IV PDE, has generated interest aspotential target for the development of novel anti-asthmatic andanti-inflammatory compounds. PDE4 is known to exist as at least fourisoenzymes, each of which is encoded by a distinct gene. Each of thefour known PDE4 gene products is believed to play varying roles inallergic and/or inflammatory responses. Thus it is believed thatinhibition of PDE4, particularly the specific PDE4 isoforms that producedetrimental responses, can beneficially affect allergy and inflammationsymptoms. It would be desirable to provide a method of treatment ofrheumatoid arthritis by administering compounds and compositions thatinhibit PDE4 activity.

A major concern with the use of PDE4 inhibitors is the side effect ofemesis which has been observed for several candidate compounds asdescribed in the patents U.S. Pat. No. 5,622,977, WO 99/50262, U.S. Pat.No. 6,410,563 and U.S. Pat. No. 5,712,298. It was also described thewide variation of the severity of the undesirable side effects exhibitedby various compounds. There is a great interest and research oftherapeutic PDE4 inhibitors as described in the above mentioned patentsand references cited therein.

PRIOR ART

I) U.S. Pat. No. 6,420,385 discloses novel compounds of the formula(IIa),

wherein:

represents

or

X is O, S or NR₅; each of R₁ and R₂ independently represent —Y or —Z—Yand R₃ and R₄ each independently represent —Z—Y or R₃ is a hydrogenradical; provided that R₄ is other than a substituted-aryl,(substituted-aryl)methyl or (substituted-aryl)ethyl radical, whereineach Z is independently optionally substituted alkyl, alkenyl, alkynyl,heterocyclyl, aryl or heteroaryl; Y is independently a hydrogen; halo,cyano, nitro, etc., R₅ is independently a hydrogen, optionallysubstituted alkyl, alkenyl, alkynyl etc., each of R₁₁ and R₁₂independently represent optionally substituted aryl or heteroaryl. Anexample of these compounds is shown in the formula (IIb),

II) U.S. Pat. No. 5,728,704 discloses novel pyrimidines of the formula(I),

wherein R¹ is hydrogen, CF₃, (C₁-C₆)alkyl, (C₁-C₆)alkyl-S—(C₁-C₆)alkyl,(C₁-C₆)alkyl-SO—(C₁-C₆)alkyl, (C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl,hydroxy-(C₁-C₆)alkyl, dihydroxy-(C₁-C₆)alkyl, C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl-(C₁-C₆)alkyl, aryl selected from phenyl andnaphthyl, aryl-(C₁-C₆)alkyl; R² and R³ are independently selected fromhydrogen, (C₁-C₆)alkyl, phenyl and phenyl-(C₁-C₄)alkyl, or R² and R^(□)form, together with the nitrogen to which they are attached, a cyclicgroup selected from azetidino, pyrrolidino, piperidino, piperazino andmorpholino, wherein said cyclic group may optionally be substituted; R⁴is hydrogen, chloro, bromo, cyano, nitro, trifluoromethyl, amino,(C₁-C₆)alkyl, (C₁-C₆)hydroxyalkyl, (C₁-C₆)alkoxy, phenyl, naphthyl orfuryl, wherein said phenyl, naphthyl and furyl may optionally besubstituted; R⁵ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,trifluoromethyl, (C₁-C₆)hydroxyalkyl, —S—(C₁-C₆)alkyl, —SO—(C₁-C₆)alkyl,—SO₂—(C₁-C₆)alkyl, phenyl or furyl.III) U.S. Pat. Nos. 6,420,385 and 6,410,729 discloses novel compounds ofthe formula (IIe),

wherein R₁ and R₂ are each independently —Z—Y, preferably R₂ is aradical of hydrogen, C₁-C₄ alkyl, halo, hydroxy, amino, etc., Z isindependently a bond, alkyl, alkenyl etc., Y is independently a hydrogenradical, halo, nitro radical; R₂₀ is independently (1) alkyl, alkenyl,heterocyclyl radical, aryl, heteroaryl; R₂₁ is independently hydrogenradical, R₂₀; R₂₂ is independently hydrogen, heterocyclyl, aryl orheteroaryl.IV) U.S. Pat. No. 7,317,014 discloses novel compounds of the formula(I),

wherein R1, R2, R3 and R4 may be same or different and independentlyrepresent hydrogen, hydroxy, nitro, nitroso, formyl, azido, halo orsubstituted or unsubstituted groups selected from alkyl, haloalkyl,alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroaryl, heterocyclyl,acyl, acyloxy, cycloalkyl, amino, hydrazine, monoalkylamino,dialkylamino, acylamino, alkylsulfonyl, arylsulfonyl, alkylsulfinyl,arylsulfinyl, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl,alkoxyalkyl, sulfamoyl, carboxylic acid and its derivatives; Arepresents pyrimidine derivative of the formula.

Wherein R5, R6, R7 may be same or different and represent, hydrogen,nitro, nitroso, formyl, azido, halo, or substituted or unsubstitutedgroups selected from alkyl, alkoxy, acyl, cycloalkyl, haloalkyl, amino,hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsulfonyl,alkylsulfinyl, arylsulfonyl, arylsulfinyl, alkylthio, arylthio,alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl, carboxylic acidand its derivatives; the pyrimidine group may be attached to the phenylring through carbon or nitrogen atom.V) U.S. Pat. No. 5,622,977 describes tri-substituted aryl derivative PDEIV inhibitors with the following general structure.

Wherein Y is halogen or OR₁, where R₁ is a substituted or unsubstitutedalkyl; X is —O—, —S—, or —N(R₈)—, where R₈ is hydrogen or alkyl; R₂ issubstituted or unsubstituted alkyl, alkenyl, cycloalkyl or cycloakenyl;R₃ hydrogen, halogen or OR₉, where R₉ is hydrogen or substituted orunsubstituted alkyl, alkenyl, alkoxyalkyl, or alkanoyl, formylcarboxamide or thiocarboxamido; R₄ and R₅ which may be same ordifferent, are each —(CH₃)_(n)Ar, where Ar is a monocyclic or bicyclicaryl group or monocyclic or bicyclic heteroaryl and n is integer of 0 to3; R₆ is hydrogen or substituted or unsubstituted alkyl; R₇ is hydrogenor substituted or unsubstituted alkyl.VI) WO 99/50262 describes PDE IV inhibitors, tri-aryl ethane derivativesof the following general structure.

Wherein, L represents hydrogen or substituted or unsubstituted alkyl oraryl; A and B represent independently substituted or unsubstitutedcarbons joined together by single or double bond; D is oxygen orsubstituted or unsubstituted nitrogen; Q is substituted or unsubstitutedaryl; R1, R2, R3 each independently represent hydrogen, halo, hydroxy,substituted or unsubstituted alkyl, alkoxy and the like.VII) U.S. Pat. No. 6,410,563 describes 8-arylquinoline compounds thatare PDE4 inhibitors.

Wherein, S₁, S₂ and S₃ each indepentyl represent hydrogen, halo,hydroxy, substituted or unsubstituted alkyl, alkoxy, and the like; R1,R2, R3 each independently represent hydrogen, halogen, substituted orunsubstituted alkyl, alkoxy, aryl, heteroaryl, substituted orunsubstituted sulfonamide, and the like; A represent substituted orunsubstituted carbon.VIII) U.S. Pat. No. 5,712,298 describes other PDE4 inhibitors asfollows.

Wherein, R1, R2 each independently represent substituted orunsubstituted hydroxy, alkoxy, and the like, R3 represently substitutedor unsubstituted phenyl or aryl, and the like.IX) WO2007/083182 discloses novel heterocyclic compounds of the formula(I), used for treatment of pain disorder, inflammation and immunologicaldiseases, those mediated by cytokines such as TNF-α, IL-1β and IL-6.

Wherein, A represents substituted or unsubstituted groups selected fromaryl; wherein B represents substituted or unsubstituted groups selectedfrom aryl or pyridyl. When B is aryl or pyridyl then R representssubstituted or unsubstituted groups selected from aryl, heteroarylgroups, the heteroaryl groups may be selected from pyridyl, thienyl,furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl,tetrazolyl, pyrimidinyl, pyrazine, benzofuranyl, benzimidazolyl,benzothiazolyl and the like, aryloxy and heterocyclyl groups such asmorpholine, piperazine, piperidine, pyrrolidine, thiazolidine and thelike; R1, R2, R3 and R4 represents hydrogen, hydroxy, nitro, azido,halogens, substituted or unsubstituted groups selected from alkyl,haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, alkylthio,alkoxycarbonyl, alkoxyalkyl, sulfamoyl, —SO2NHNH2, —SO2Cl, carboxylicacid and its derivatives.

OBJECTIVES

We have focused our research to identify cytokine inhibitorspredominantly acting through the inhibition of the TNF-α, which aredevoid of any side effects normally associated with TNF-α inhibitors andto identify novel small molecule anticancer agents. Our sustainedefforts have resulted in novel heterocyclic compounds of the formula(I). The derivatives may be useful in the treatment of inflammation,cancer and immunological diseases. Particularly the compounds of thepresent invention are useful for the treatment of immunological diseasesthose mediated by cytokines such as TNF-α, IL-1, IL-6, IL-β, IL-8; IL-12and inflammation. More particularly, the compounds of the presentinvention are useful as PDE4 inhibitors, and are useful for treatingPDE4 mediated diseases. The compounds of the present invention are alsouseful in the treatment of rheumatoid arthritis; osteoporosis; multiplemyeloma; uveititis; acute and chronic myelogenous leukemia; ischemicheart disease; atherosclerosis; ischemic-induced cell damage; pancreaticβ-cell destruction; osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease; adult respiratory distresssyndrome (ARDS); asthma, chronic obstructive pulmonary disorder (COPD),psoriasis; Crohn's disease; allergic, rhinitis; ulcerative colitis;anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia;bone resorption diseases; ischemia reperfusion injury; brain trauma;multiple sclerosis; sepsis; septic shock; toxic shock syndrome; feverand myalgias due to infection.

SUMMARY

Described are novel heterocyclic compounds of the formula (I),

their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs,solvates, pharmaceutically acceptable salts and pharmaceuticalcompositions, metabolites and prodrugs thereof, wherein, A representssubstituted or unsubstituted aryl groups; B represents substituted orunsubstituted groups selected from aryl or pyridyl; X represents carbonor nitrogen; R represents substituted or unsubstituted groups selectedfrom azido, halogens, alkyl, alkoxy, acyl, cycloalkyl, haloalkyl, amino,hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsulfonyl,alkylsulfinyl, arylsulfonyl, arylsulfinyl, alkoxycarbonyl,aryloxycarbonyl, alkoxyalkyl, sulfamoyl, aryl, heteroaryl, aryloxy,—OSO₂R′ and heterocyclyl groups; wherein R′ represents substituted orunsubstituted groups selected from alkyl, aryl, alkyldialkylamino,haloalkyl, heterocyclyl and heteroaryl groups; R₁ represents hydrogen,hydroxy, nitro, formyl, azido, halogens, substituted or unsubstitutedgroups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy,amino, hydrazine, monoalkylamino, dialkylamino, acylamino,alkylsulfonyl, alkylsulfinyl, heterocyclylsulfonyl, alkylthio,alkoxycarbonyl, alkoxyalkyl, sulfamoyl, —SO₂NHNH₂, —SO₂Cl, carboxylicacid and its derivatives; R₂ represents hydrogen, hydroxy, nitro,formyl, azido, halogens, substituted or unsubstituted groups selectedfrom alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine,monoalkylamino, dialkylamino, acylamino, alkylsulfonyl, alkylsulfinyl,alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, —SO₂NHNH₂, —SO₂Cl,carboxylic acid and its derivatives; R₃ represents hydrogen, hydroxy,nitro, formyl, azido, halogens, substituted or unsubstituted groupsselected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino,hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsulfonyl,alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl,—SO₂NHNH₂, —SO₂Cl, carboxylic acid and its derivatives; R₄ representshydrogen, hydroxy, nitro, formyl, azido, halogens, substituted orunsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl,aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino,acylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl,alkoxyalkyl, sulfamoyl, —SO₂NHNH₂, —SO₂Cl, carboxylic acid and itsderivatives.

DETAILED DESCRIPTION

Described are novel heterocyclic compounds of the formula (I),

their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs,solvates, pharmaceutically acceptable salts, compositions, metabolitesand prodrugs thereof, wherein A represents substituted or unsubstitutedaryl group;

B represents substituted or unsubstituted groups selected from aryl orpyridyl;

X represents carbon or nitrogen atom;

R represents substituted or unsubstituted groups selected from azido;halogens; linear or branched alkyl groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl,hexyl and the like; alkoxy groups such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, t-butoxy and the like; haloalkyl groupssuch as dichloromethyl, difluoromethyl, trifluoromethyl, trichloromethyland the like; acyl groups such as acetyl, propanoyl and the like;cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and thelike; amino; hydrazine; monoalkylamino; dialkylamino; acylamino groupssuch as acetylamino, propanoylamino and the like; alkylsulfonyl groupssuch as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like;alkylsulfinyl; arylsulfonyl; arylsulfinyl; alkoxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl and the like; aryloxycarbonyl;alkoxyalkyl; sulfamoyl; aryl groups such as phenyl, naphthyl and thelike; heteroaryl groups such as pyridyl, thienyl, furyl, pyrrolyl,pyrazolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, triazolyl,tetrazolyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzimidazolyl andbenzothiazolyl; aryloxy; —OSO₂R′ and heterocyclyl groups such asmorpholine, thiomorpholine, piperazine, piperidine, piperidin-4-one,pyrrolidine, pyrrol-2,5-dione, thiazolidine, 1-oxido-thiazolidine and1,1-dioxido-1,3-thiazolidine; the heterocyclyl group is optionallysubstituted with substitutents independently selected from substitutedor unsubstituted alkyl, aryl, heteroaryl, aralkyl (—CH₂-aryl),alkylheteroaryl (—CH₂-heteroaryl), substituted arylcarbonyl (—CO—Ar),heteroarylcarbonyl (—CO-heteroaryl), heteroarylthiocarbonyl(—CS-heteroaryl), cycloalkylcarbonyl (—CO-cycloalkyl), cyanoalkyl,—O-methyloxime, alkylsulfonyl, haloalkylsulfonyl, haloacyl, —SO₂Cl,formyl, hydroxamic acid and another substituted or unsubstitutedheterocyclyl group; the attachment of the heterocyclyl group to thepyrimidine ring is through carbon or nitrogen; wherein R′ representssubstituted or unsubstituted groups selected from alkyl, aryl,alkyldialkylamino, haloalkyl, heterocyclyl and heteroaryl groups;

R₁ represents hydrogen; hydroxy; nitro; formyl; azido; halogens;substituted or unsubstituted groups are selected from alkyl; haloalkyl;alkoxy; aryl; aryloxy groups selected from phenoxy and naphthoxy;acyloxy groups such as MeCOO—, EtCOO— and PhCOO—; amino; hydrazine;monoalkylamino; dialkylamino; acylamino; alkylsulfonyl; alkylsulfinyl;alkylthio; alkoxycarbonyl; alkoxyalkyl; sulfamoyl; —SO₂NHNH₂; —SO₂Cl;carboxylic acid and its derivatives;

R₂ represents hydrogen; hydroxy; nitro; formyl; azido; halogens;substituted or unsubstituted groups selected from alkyl; haloalkyl;alkoxy; aryl; aryloxy; acyloxy; amino; hydrazine; monoalkylamino;dialkylamino; acylamino; alkylsulfonyl; alkylsulfinyl; alkylthio;alkoxycarbonyl; alkoxyalkyl; sulfamoyl; —SO₂NHNH₂; —SO₂Cl; carboxylicacid and its derivatives;

R₃ represents hydrogen; hydroxy; nitro; formyl; azido; halogens;substituted or unsubstituted groups selected from alkyl; haloalkyl;alkoxy; aryl; aryloxy; acyloxy; amino; hydrazine; monoalkylamino;dialkylamino; acylamino; alkylsulfonyl; alkylsulfinyl; alkylthio;alkoxycarbonyl; alkoxyalkyl; sulfamoyl; —SO₂NHNH₂; —SO₂Cl; carboxylicacid and its derivatives;

R₄ represents hydrogen; hydroxy; nitro; formyl; azido; halogens;substituted or unsubstituted groups selected from alkyl; haloalkyl;alkoxy; aryl; aryloxy; acyloxy; amino; hydrazine; monoalkylamino;dialkylamino; acylamino; alkylsulfonyl; alkylsulfinyl; alkylthio;alkoxycarbonyl; alkoxyalkyl; sulfamoyl; —SO₂NHNH₂; —SO₂Cl; carboxylicacid and its derivatives;

the groups R, R₁, R₂, R₃, R₄ and R′ are optionally substituted by one ormore substituents selected from halogens; hydroxy; nitro; cyano; ureas;azido; amino; imino-1-phenyl butanone; amide groups such as acetamide,benzamide and the like; thioamide; hydrazine; linear or branched alkylgroups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,t-butyl, n-pentyl, isopentyl, hexyl and the like; alkoxy groups such asmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxyand the like; haloalkyl groups such as dichloromethyl, difluoromethyl,trifluoromethyl, trichloromethyl and the like; acyl groups such asacetyl, propanoyl, benzoyl and the like; haloalkoxy groups such astrifluoromethoxy, trifluoroethoxy, trichloromethoxy and the like;cycloalkyl groups such as cyclopropyl, cyclobutyl and the like; haloacylgroups such as trifluoroacetyl, trichloroacetyl and the like;acyloxyacyl; heterocyclyl; aryl; heteroaryl; monoalkylamino;dialkylamino; acylamino; aryloxy groups such as phenoxy, naphthoxy andthe like; alkoxycarbonyl groups such as methoxycarbonyl andethoxycarbonyl; aryloxycarbonyl; alkylsulfonyl; haloalkylsulfonyl;—SO₂Cl; arylsulfonyl; alkylsulfinyl; arylsulfinyl; thioalkyl; thioaryl;sulfamoyl; alkoxyalkyl groups; carboxylic acids and its derivatives suchas hydroxamic acid, hydroxamates, esters, amides and acid halides; thesesubstituents are further optionally substituted with substituentsselected from hydroxy; alkoxy; halogens; alkylsulfonyl; haloalkyl; alkyland aryl group which in turn is optionally further substituted byhalogens and alkyl;

Pharmaceutically acceptable salts include alkali metals like Li, Na, andK, alkaline earth metals like Ca and Mg, salts of organic bases such asdiethanolamine, α-phenylethylamine, benzylamine, piperidine, morpholine,pyridine, hydroxyethylpyrrolidine, choline hydroxyethylpiperidine andthe like, ammonium or substituted ammonium salts and aluminum salts.Salts also include amino acid salts such as glycine, alanine, cystine,cysteine, lysine, arginine, phenylalanine, guanidine etc. Salts mayinclude acid addition salts where appropriate, which are, sulphates,nitrates, phosphates, perchlorates, borates, hydrohalides, acetates,tartrates, maleates, citrates, succinates, palmoates,methanesulphonates, tosylates, benzoates, salicylates,hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates,ketoglutarates and the like. Pharmaceutically acceptable solvates may behydrates or comprising other solvents of crystallization such asalcohols.

The term analog includes a compound, which differs from the parentstructure by one or more C, N, O or S atoms. Hence, a compound in whichone of the N atoms in the parent structure is replaced by an S atom isan analog of the former.

The term stereoisomer includes isomers that differ from one another inthe way the atoms are arranged in space, but whose chemical formulas andstructures are otherwise identical. Stereoisomers include enantiomersand diastereoisomers.

The term tautomers include readily interconvertible isomeric forms of acompound in equilibrium. The enol-keto tautomerism is an example.

The term polymorphs include crystallographically distinct forms ofcompounds with chemically identical structures.

The term pharmaceutically acceptable solvates includes combinations ofsolvent molecules with molecules or ions of the solute compound.

The term derivative refers to a compound obtained from a compoundaccording to formula (I), an analog, tautomeric form, stereoisomer,polymorph, hydrate, pharmaceutically acceptable salt or pharmaceuticallyacceptable solvate thereof, by a simple chemical process converting oneor more functional groups, such as, by oxidation, hydrogenation,alkylation, esterification, halogenation, and the like.

A term once described, the same meaning applies for it, through thepatent

Representative Compounds Include:

-   1.    N-({4-[4-Amino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl]phenyl}sulfonyl)acetamide;-   2.    4-{4-Amino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}-N-methylbenzenesulfonamide;-   3.    4-{4-Chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonyl    chloride;-   4.    4-{4-Chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}-N-methylbenzenesulfonamide;-   5.    4-{4-(Methylamino)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}-N-methylbenzenesulfonamide;-   6.    N-[(4-{4-(Methylamino)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}phenyl)sulfonyl]acetamide;-   7.    4-{4-Hydrazino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonohydrazide;-   8.    4-[4-(4-Fluorophenyl)-6-hydrazino-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonohydrazide;-   9.    N-[(4-{4-Hydrazino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)    pyrimidin-5-yl}phenyl)sulfonyl]acetamide;-   10.    4-{4-Hydrazino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimdin-5-yl}-N-methylbenzenesulfonamide;-   11.    4-Hydrazino-5-phenyl-6-pyridin-3-yl-2-(trifluoromethyl)pyrimidine;-   12.    4-Hydrazino-5-phenyl-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidine;-   13.    5-(4-Fluorophenyl)-4-hydrazino-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidine;-   14.    2,2,2-Trifluoro-N-[5-(4-fluorophenyl)-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidin-4-yl]acetohydrazide;-   15.    N′-[5-Phenyl-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidin-4-yl]acetohydrazide;-   16.    2,2,2-Trifluoro-N′-[5-phenyl-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidin-4-yl]acetohydrazide;-   17.    N-[(4-{4-Chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}phenyl)sulfonyl]acetamide;-   18.    6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-ylnapthalenesulfonate;-   19.    6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-3-chloropropane-1-sulfonate;-   20.    6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-3-(trifluoromethyl)benzenesulfonate;-   21.    6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-2-(trifluoromethyl)benzenesulfonate;-   22.    6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-4-methylbenzenesulfonate;-   23.    6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-4-nitrobenzenesulfonate;-   24.    6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-4-trifluoromethoxybenzenesulfonate;-   25.    6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl    thiophene-2-sulfonate;-   26.    6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-4-fluorobenzenesulfonate;-   27.    6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-2-fluorobenzenesulfonate;-   28.    6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-(dimethylamino)propanesulfonate;-   29.    6-[4-(Methylsulfonyl)phenyl]-5-phenyl-4-(N-benzyl-piperazin-1-yl)-2-(trifluoromethyl)pyrimidine;-   30.    4-[4-(4-Fluorophenyl)-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   31.    4-[5-(4-Fluorophenyl)-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide;-   32.    N-Methyl-4-[4-(methylsulfonyl)phenyl]-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   33.    4-[4-(Methylsulfonyl)phenyl]-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   34.    4-{4-(Morpholin-4-yl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}-N-methylbenzenesulfonamide;-   35.    5-{4-[4-(Methylsulfonyl)phenyl]-6-piperidin-1-yl-2-(trifluoromethyl)pyrimidin-5-yl}-N-methylbenzenesulfonamide;-   36.    4-[4-(Methylsulfonyl)phenyl]-6-{4-[(5-methylpyrazin-2-yl)carbonyl]piperazin-1-yl}-5-phenyl-2-(trifluoromethyl)pyrimidine;-   37.    6-[4-(Methylsulfonyl)phenyl]-5-phenyl-4-{4-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperazin-1-yl}-2-(trifluoromethyl)pyrimidine;-   38.    6-[4-(Methylsulfonyl)phenyl]-4-[4-(5-nitro-2-furoyl)piperazin-1-yl]-5-phenyl-2-(trifluoromethyl)pyrimidine;-   39.    N-Methyl-4-{4-[4-(5-nitro-2-furoyl)piperazin-1-yl]-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;-   40.    4-{5-[4-Fluorophenyl]-4-[4-(5-nitro-2-furoyl)piperazin-1-yl]-2-(trifluoro    methyl)pyrimidin-6-yl}benzenesulfonamide;-   41.    4-{6-[4-Fluorophenyl]-4-[4-(5-nitro-2-furoyl)piperazin-1-yl]-2-(trifluoro    methyl)pyrimidin-5-yl}benzenesulfonamide;-   42.    6-[4-(Methylsulfonyl)phenyl]-4-{4-[(5-nitro-1H-pyrazol-3-yl)carbonyl]piperazin-1-yl}-5-phenyl-2-(trifluoromethyl)pyrimidine;-   43.    5,6-Diphenyl-4-[4-(5-nitro-2-furoyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidine;-   44.    5-[4-Fluorophenyl]-4-[4-(5-nitro-2-furoyl)piperazin-1-yl]-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidine;-   45.    6-[4-(Methylsulfonyl)phenyl]-5-phenyl-4-[4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidine;-   46.    4-[4-(Methylsulfonyl)phenyl]-5-phenyl-6-[4-(pyridin-4-ylmethyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidine;-   47.    6-[4-(Methylsulfonyl)phenyl]-4-{4-[(5-nitro-2-thienyl)methyl]piperazin-1-yl}-5-phenyl-2-(trifluoromethyl)pyrimidine;-   48.    4,5-Diphenyl-6-(4-pyridin-2-yl-piperazin-1-yl)-2-(trifluoromethyl)pyrimidine;-   49.    4-[4-(Methylsulfonyl)phenyl]-5-phenyl-6-(4-pyridin-2-yl-piperazin-1-yl)-2-(trifluoromethyl)pyrimidine;-   50.    3-[4-(4-Fluorophenyl)-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   51.    3-[4-Phenyl-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   52.    3-[5-(3-Aminosulfonylphenyl)]-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide;-   53.    3-[4-(4-Fluorophenyl)-6-(4-pyridin-2-ylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   54.    3-[4-(4-Fluorophenyl)-6-(4-pyrimidin-2-ylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   55.    3-[5-Phenyl-6-(1,3-thiazolidin-3-yl)-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide;-   56.    3-[6-[(4-Hydroxycyclohexyl)amino]-5-(3-aminosulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide;-   57.    3-[6-(4-Pyrimidin-2-ylpiperazin-1-yl)]-4-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   58.    3-[6-(4-Pyridin-2-ylpiperazin-1-yl)]-4-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   59.    Ethyl-1-[5-(3-aminosulfonylphenyl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl]piperidine-4-carboxylate;-   60.    3-[4-[(4-Hydroxycyclohexyl)amino]-6-(4-fluorophenyl)-2-(trifluoro    methyl)pyrimidin-5-yl]benzenesulfonamide;-   61. Ethyl    1-[6-phenyl-5-(3-aminosulfonylphenyl)1-2-(trifluoromethyl)pyrimidin-4-yl]piperidine-4-carboxylate;-   62.    4-[6-Phenyl-5-(3-morpholinosulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]morpholine;-   63.    3-[4-(4-Fluorophenyl)-6-morpholin-4-yl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   64.    (3R)-1-[6-(4-Fluorophenyl)-5-(3-aminosulfonylphenyl)-2-(trifluoro    methyl)pyrimidin-4-yl]pyrrolidin-3-ol;-   65. Ethyl (2S,4R)-4-hydroxy-1-[6-(4-fluorophenyl)-5-(3-aminosulfonyl    phenyl)-2-(trifluoromethyl)pyrimidin-4-yl]pyrrolidine-2-carboxylate;-   66.    4-[4-(2,6-Dimethoxypyrimidin-4-yl)piperazin-1-yl]-5-(3-aminosulfonyl    phenyl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidine;-   67.    5-(4-Fluorophenyl)-4-(4-pyridin-2-ylpiperazin-1-yl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidine;-   68.    4-(4-Methylsulfonylphenyl)-5-(4-fluorophenyl)-6-(4-pyrimidin-2-yl    piperazin-1-yl)-2-(trifluoromethyl)pyrimidine;-   69.    4-[5-(4-Fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-4-yl]piperazine-1-carbaldehyde;-   70.    1′-[5-(4-Fluorophenyl)-6-(4-methylsulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]-1,4′-bipiperidine;-   71.    3-[4-(4-Fluorophenyl)-6-(1,4′-bipiperidin-1′-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   72.    3-[4-(2-Furoyl)piperazin-1-yl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   73.    5-(3-Aminosulfonylphenyl)-4-(4-fluorophenyl)-2-(trifluoromethyl)-6-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}pyrimidine;-   74.    5-(4-Fluorophenyl)-4-(4-methylsulfonylphenyl)-2-(trifluoromethyl)-6-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}pyrimidine;-   75.    3-[4-(4-Fluorophenyl)-6-(1,3-thiazolidin-3-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   76.    1-[5-[3-(Aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl]pyrrolidine-2-carboxamide;-   77.    5-(3-Aminosulfonylphenyl)-4-(4-fluorophenyl)-2-(trifluoromethyl)-6-{4-[(trifluoromethyl)sulfonyl]piperazin-1-yl}pyrimidine;-   78.    3-[4-[4-(Methylsulfonyl)piperazin-1-yl]-6-(4-fluorophenyl)-2-(trifluoro    methyl)pyrimidin-5-yl]benzenesulfonamide;-   79.    3-[4-[4-(Cyanomethyl)piperazin-1-yl]-6-(4-fluorophenyl)-2-(trifluoro    methyl)pyrimidin-5-yl]benzenesulfonamide;-   80.    3-[4-(4-Fluorophenyl)-6-(1H-imidazol-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   81.    5-(6-(4-Fluorophenyl)-4-(1H-imidazol-1-yl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidine;-   82.    N-({3-[6-(4-Fluorophenyl)-4-(4-pyridin-2-ylpiperazin-1-yl)-2-(trifluoro    methyl)pyrimidin-5-yl]phenyl}sulfonyl)propanamide;-   83.    3-[6-(4-Fluorophenyl)-4-(morpholin-4-yl)-2-(trifluoromethyl)pyrimidin-5-yl]-N-cyclopropylbenzenesulfonamide;-   84.    3-[6-(4-Fluorophenyl)-4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   85.    3-[6-(4-Fluorophenyl)-4-(2-methyl-5-nitro-1H-imidazol-1-yl)-2-(trifluoro    methyl)pyrimidin-5-yl]benzenesulfonamide;-   86.    3-[6-(4-Fluorophenyl)-4-(4-oxopiperidin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   87.    3-[4-(Cyclopropylamino)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   88.    3-[6-(4-Fluorophenyl)-4-(4-phenyl-1H-imidazol-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   89.    3-[6-(4-Fluorophenyl)-4-(2,6-dimethylmorpholin-4-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   90.    3-[6-(4-Fluorophenyl)-4-(2,6-dimethylpiperazin-4-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   91.    3-[6-(4-Fluorophenyl)-4-(2-methylpiperazin-4-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   92.    3-[6-(4-Fluorophenyl)-4-(1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   93.    3-[6-(4-Fluorophenyl)-4-(3-amino-1H-pyrazol-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   94.    3-[6-(4-Fluorophenyl)-4-(thiomorpholin-4-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   95.    3-[6-(4-Fluorophenyl)-4-({2-[(methylsulfonyl)amino]ethyl}amino)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   96.    3-{6-(4-Fluorophenyl)-4-[3-methyl-4-(methylsulfonyl)piperazin-1-yl]-2-trifluoromethylpyrimidin-5-yl}benzenesulfonamide;-   97.    3-{6-(4-Fluorophenyl)-4-[3-(hydroxymethyl)-4-(4-fluorophenyl)piperidin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;-   98.    3-[4-Morpholin-4-yl-2-(trifluoromethyl)-6-phenyl-pyrimidin-5-yl]benzenesulfonamide.-   99.    3-[6-(4-Fluorophenyl)-4-(2-morpholin-4-ylethoxy)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   100.    3-{4-[4-(2-Cyanoethyl)piperazin-1-yl]-6-(4-fluorophenyl)-2-(trifluoro    methyl)pyrimidin-5-yl}benzenesulfonamide;-   101.    3-{6-(4-Fluorophenyl)-4-[3-methyl-4-(pyridin-2-yl-methyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;-   102.    3-{6-(4-Fluorophenyl)-4-[3-methyl-4-(3-methoxybenzyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;-   103.    3-(6-(4-Fluorophenyl)-4-[4-(pyridin-2-yl-methyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-ylbenzenesulfonamide;-   104.    3-(6-(4-Fluorophenyl)-[4-(3-methoxybenzyl)piperazin-1-yl]-2-(trifluoro    methyl)pyrimidin-5-yl)benzenesulfonamide;-   105.    3-{6-(4-Fluorphenyl)-[4-(2-hydroxyethyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;-   106.    3-(6-(4-Fluorophenyl)-4-[4-(1H-imidazol-1-ylcarbonothioyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl)benzenesulfonamide;-   107.    3-[4-(1,1-Dioxido-1,3-thiazolidin-3-yl)-6-(4-fluorophenyl)-2-(trifluoro    methyl)pyrimidin-5-yl]benzenesulfonamide;-   108.    3-[6-(4-Fluorophenyl)-4-(1-oxido-1,3-thiazolidin-3-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   109.    3-{6-(4-Fluorophenyl)-4-[4-(trifluoroacetyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;-   110.    3-{6-(4-Fluorophenyl)-4-[4-(2-fluorobenzoyl)piperazin-1-yl]-2-trifluoromethylpyrimidin-5-yl}benzenesulfonamide;-   111.    4-{-[3-(Aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}piperazine-1-sulfonyl    chloride;-   112.    3-(4-[4-(Cyclopropylcarbonyl)piperazin-1-yl]-6-(4-fluorphenyl)-2-(trifluoromethyl)-pyrimidin-5-yl)benzenesulfonamide;-   113.    3-{6-(4-Fluorophenyl)-4-[4-(methoxyimino)piperidin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;-   114.    3-{6-(4-Fluorophenyl)-4-[(3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)amino]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;-   115.    3-{4-[(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)amino]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;-   116.    3-[6-{4-[5-(Trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-4-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide;-   117.    3-[6-{4-[2,6-Dimethoxypyrimidin-4-yl]piperazin-1-yl}-4-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   118.    3-[6-{4-[5-(Nitro)pyridin-2-yl]piperazin-1-yl}-4-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   119.    3-[6-{4-[5-(Amino)pyridin-2-yl]piperazin-1-yl}-4-[4-fluorophenyl]-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   120.    4-[5-(Acetylamino)pyridin-2-yl]piperazin-1-yl-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidine;-   121.    N-({3-[4-Pyridin-2-yl]piperazin-1-yl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]phenyl}sulfonyl)acetamide;-   122.    4-Fluorophenyl-5-(3-propionylaminosulfonylphenyl)-6-[4-pyridin-2-yl]piperazin-1-yl)-2-(trifluoromethyl)pyrimidine;-   123.    1-{5-[3-(Aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}piperidine-4-carboxylic    acid;-   124.    4-[4-(Methoxyaminocarbonyl)piperidin-1-yl]-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidine;-   125.    1-{5-[3-(Aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}-N-hydroxypiperidine-4-carboxamide;-   126.    Methyl-3-methoxy-4-({6-[4-(methylsulfonyl)phenyl]-5-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}oxy)benzoate;-   127.    3-Methoxy-4-({6-(4-fluorophenyl)-5-[3-(aminosulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-4-yl}oxy)-N-methoxybenzamide;-   128.    4-{[5-(4-Fluorophenyl)-6(4-methylsulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}-N,3-dimethoxybenzamide;-   129.    5-Amino-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-methyl-1H-pyrazole-4-carbonitrile;-   130.    Ethyl-5-amino-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-1H-pyrazole-4-carboxylate;-   131.    5-Amino-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrazole-4-carbonitrile;-   132.    3-t-Butyl-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrazol-5-amine;-   133.    4-(3,5-Dimethyl-1H-pyrazol-1-yl)-5,6-diphenyl-2-(trifluoromethyl)pyrimidine;-   134.    3-[4-(5-Amino-4-cyano-3-methyl-1H-pyrazol-1-yl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   135.    Ethyl-5-amino-1-[5-[3-(aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-1H-pyrazole-4-carboxylate;-   136.    4-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-6-[5-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidine;-   137.    5-Amino-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrazole-4-carbothioamide;-   138.    (3Z)-4,4,4-Trifluoro-1-phenylbutane-1,3-dione-3-{[5-phenyl-6-(4-methylsulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]hydrazone};-   139.    N-{1-[5,6-Diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-t-butyl-1H-pyrazol-5-yl}-4-methoxybenzamide;-   140.    N-{1-[5,6-Diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-t-butyl-1H-pyrazol-5-yl}-3-fluorobenzamide;-   141.    N-{1-[5,6-Diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-t-butyl-1H-pyrazol-5-yl}-4-(trifluoromethyl)benzamide;-   142.    Ethyl-5-amino-1-[5-phenyl-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-1H-pyrazole-4-carboxylate;-   143.    5-Amino-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-N-phenyl-1H-pyrazole-4-carboxamide;-   144.    5-Amino-N-(4,5-dimethylphenyl)-1-[5-(4-fluorophenyl)-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-1H-pyrazole-4-carboxamide;-   145.    1-(2,6-Dichlorophenyl)-3-{1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-t-butyl-1H-pyrazol-5-yl}urea;-   146.    4-[4-(Methylthio)phenyl]-5,6-diphenyl-2-(trifluoromethyl)pyrimidine;-   147.    5-Phenyl-4-[4-(methylsulfonyl)phenyl]-6-[4-(methylthio)phenyl]-2-(trifluoromethyl)pyrimidine;-   148.    3-[4-(3,5-Dimethylpiperazin-1-yl)-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   149.    3-{4-[(3S)-3-Methylpiperazin-1-yl]-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;-   150.    3-[4-(2,6-Dimethylmorpholin-4-yl)-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   151.    2,2,2-Trifluoro-N-({3-[6-phenyl-4-(4-(trifluoroacetyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]phenyl}sulfonyl)acetamide;-   152.    3-[4-(2-Amino-1H-imidazol-1-yl)-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   153.    5-(4-Chlorophenyl)-6-[4-(methylsulfonyl)phenyl]-4-(piperazin-1-yl)-2-(trifluoromethyl)pyrimidine;-   154.    4,5-Diphenyl-6-[4-(methylsulfonyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidine;-   155.    5-(4-Chlorophenyl)-6-[4-(methylsulfonyl)phenyl]-4-(morpholin-1-yl)-2-(trifluoromethyl)pyrimidine;-   156.    2-Chloro-4-fluoro-5-({4-[6-(4-methylsulfonylphenyl)-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}sulfonyl)benzoic    acid;-   157.    2-Chloro-4-fluoro-5-({4-[6-(4-methylsulfonylphenyl)-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}sulfonyl)benzoic    acid sodium salt;-   158.    4-{4-[(2-Chloro-4-fluorophenyl)sulfonyl]piperazin-1-yl}-6-(4-methylsulfonylphenyl)-5-phenyl-2-(trifluoromethyl)pyrimidine;-   159. 4-(4-Methylsulfonylphenyl)-5-phenyl-6-[4-(4-chlorophenyl,    phenyl methyl))piperazin-1-yl]-2-(trifluoromethyl)pyrimidine;-   160. Ethyl    4-[5-phenyl-6-(4-methylsulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]piperazine-1-carboxylate;-   161. t-Butyl    4-[5-phenyl-6-(4-methylsulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]piperazine-1-carboxylate;-   162.    6-(4-Methylphenyl)-5-phenyl-4-(4-(pyrimidin-2-yl)-piperazin-1-yl)-2-(trifluoromethyl)pyrimidine;-   163.    6-(4-Fluorophenyl)-5-phenyl-4-(1,3-thiazolidin-3-yl)-2-(trifluoromethyl)pyrimidine;-   164.    6-(4-Fluorophenyl)-5-phenyl-4-(4-(pyrimidin-2-yl)-piperazin-1-yl-2-(trifluoromethyl)pyrimidine;-   165.    3-[6-(4-Fluorophenyl)-4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   166.    6-(4-Fluorophenyl)-N-(4-methylpiperazin-1-yl)-5-phenyl-2-(trifluoro    methyl)pyrimidin-4-amine;-   167.    3-[4-(1H-imidazol-1-yl)-5-phenyl-2-(trifluoromethyl)pyrimidin-6-yl]benzenesulfonamide;-   168.    3-[4-(4-Acetylpiperazin-1-yl)-6-(4-Fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   169.    1-{5-[3-(Aminosulfonyl)phenyl]-6-phenyl-2-(trifluoromethyl)pyrimidin-4-yl}piperidine-4-carboxylic    acid;-   170.    3-[6-(4-Fluorophenyl)-4-(thiomorpholin-4-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   171.    N-({3-[4-(4-Acetylpiperazin-1-yl)-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]phenyl}sulfonyl)acetamide;-   172.    3-[4-(1-Oxido-1,3-thiazolidin-3-yl)-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   173.    3-{6-Phenyl-4-[4-(trifluoroacetyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;-   174.    3-[4-(Cyclopropylamino)-6-(4-methylsulfonylphenyl)-2-(trifluoromethyl)pyrimidin-5-yl]-N-methylbenzenesulfonamide;-   175.    N-Cyclopropyl-6-(4-fluorophenyl)-5-phenyl-2-(trifluoromethyl)pyrimidin-4-amine;-   176.    5-Phenyl-6-(4-methylphenyl)-2-(trifluoromethyl)-4-{4-[5-(trifluoro    methyl)pyridin-2-yl]piperazin-1-yl}pyrimidine;-   177.    1-[6-(4-Methylphenyl)-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]piperidin-4-one;-   178.    3-{4-[4-(Hydroxymethyl)piperidin-1-yl]-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;-   179.    3-[6-Phenyl-4-(4-oxopiperidin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   180.    3-(4-[4-(2-Furoyl)piperazin-1-yl]-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl)benzenesulfonamide;-   181.    6-(4-Methylphenyl)-5-phenyl-4-[4-(2-propylpentanoyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidine;-   182.    N-Cyclopropyl-6-(4-methylphenyl)-5-phenyl-2-(trifluoromethyl)pyrimidin-4-amine;-   183.    4-[6-(4-Fluorophenyl)-4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   184.    4-[6-(4-Fluorophenyl)-4-(morpholin-4-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   185.    3-[4-(2-Methyl-1H-imidazol-1-yl)-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;-   186.    4-{5-[3-(Aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}piperazine-1-sulfonyl    chloride;-   187.    3-(4-[4-(Cyclopropylcarbonyl)piperazin-1-yl]-6-(4-fluorphenyl)-2-(trifluoromethyl)-pyrimidin-5-yl)benzenesulfonamide;-   188.    3-[4-(Morpholin-N-yl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]-N-cyclopropylbenzenesulfonamide    and-   189.    6-[4-(Methylsulfonyl)phenyl]-5-phenyl-4-[4-(2-thienylcarbonyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidine.

According to another embodiment of the present invention, there isprovided a process for the preparation of novel heterocyclic compoundsof the formula (I),

wherein B represents pyridine and R represents a halogen atom and theymay be prepared by converting the compound of formula (Ia), wherein allsymbols are as defined earlier.

The compound of formula (Ia) is prepared according, to the proceduredescribed in our PCT/IB03/01289.

The conversion of the compound of formula (Ia) is carried out usinghalogenating agents such as phosphorus oxychloride, thionyl chloride,phosphorus trichloride, phosphorus pentachloride and the like in thepresence or absence of solvents such as toluene, xylene,tetrahydrofuran, dioxane, chloroform, dichloromethane, dichloroethane,o-dichlorobenzene, diphenyl ether and the like or a mixture thereof, inpresence or absence of a catalytic amount of dimethylformamide orN,N-dimethylaniline or N,N-diethylaniline and the like. The reaction iscarried out at a temperature in the range of 20° C. to refluxtemperatures for a period in the range of 2 to 12 hours.

In yet another embodiment of the present invention, there is provided aprocess for the preparation of novel heterocyclic compounds of theformula (I)

wherein B represents pyridine and R represents azido or hydrazine orsubstituted hydrazine and they may be prepared by converting thecompound of the formula (Ib), wherein all the symbols are as definedearlier.

The conversion of the compound of formula (Ib) may be carried out in thepresence of one or more equivalents of a metal azide such as LiN₃, NaN₃,trialkyl silylazide and the like or hydrazine hydrate or substitutedhydrazine. The reaction may be carried out in the presence of a solventsuch as toluene, xylene, tetrahydrofuran, dioxane, chloroform,dichloromethane, dichloroethane, o-dichlorobenzene, acetone,ethylacetate, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide,ethanol, methanol, isopropylalcohol, t-butylalcohol, diphenyl ether andthe like or a mixture thereof. The reaction may be carried out at atemperature in the range of ambient temperature to reflux temperature ofthe solvent, preferably in the range of 0° C. to 100° C. The reactiontime may range from 0.5 to 18 hours.

In yet another embodiment of the present invention, there is provided aprocess for the preparation of novel heterocyclic compounds of theformula (I),

wherein R represents substituted or unsubstituted heterocyclyl groups,and the other symbols are as defined earlier and they may be prepared byconverting the compound of formula (Ib), wherein all the symbols are asdefined earlier.

The compound of formula (Ib) is prepared according to the proceduredescribed in our PCT/IB03/02879

The conversion of the compound of the formula (Ib) is carried out withappropriate heterocyclyl or protected heterocyclyl groups such asmorpholine, piperazine, benzylpiperazine, piperidine and the like; theseheterocyclyl groups may be further substituted with heteroaryl, benzyl,alkyl heteroaryl, other carboxylic acid heterocyclyl groups such asfuroic acid, thiophene carboxylic acid, pyrazine carboxylic acid and thelike in the presence or absence of appropriate solvents like toluene,xylene, tetrahydrofuran, dioxane, chloroform, dichloromethane,dichloroethane, o-dichlorobenzene, acetone, ethyl acetate, acetonitrile,N,N-dimethylformamide, dimethylsulfoxide, pyridine, diphenyl ether,ethanol, methanol, isopropylalcohol, t-butylalcohol, acetic acid,propionic acid etc and the like, or a mixture thereof or by neatreactions. The reaction may be carried out under acidic conditions usingmineral or organic acids, or basic conditions viz. carbonates,bicarbonates, hydrides, hydroxides, alkyls and alkoxides of alkalimetals and alkaline earth metals. The reaction may be carried out in thepresence of Pd₂(dba)3, BINAP, EDCI, HOBT, triethylamine,diisopropylethylamine, DMAP or by using phase transfer catalysts viz.triethylbenzylammonium chloride, tetrabutylammonium bromide,tetrabutylammonium hydrogensulphate, tricaprylylmethylammonium chloride(aliquat 336) and the like. The reaction is usually carried out undercooling to refluxing conditions. The final product is purified by usingchromatographic techniques or by recrystallization. The reaction may becarried out for a time period in the range of 2 to 20 hours.

In yet another embodiment of the present invention, there is provided aprocess for the preparation of novel heterocyclic compounds of theformula (I)

wherein R represents —OSO₂R′ and all the other symbols are as definedabove, and may be prepared by converting the compound of formula (Ia),wherein all the other symbols are as defined earlier.

The compound of the formula (Ia) is prepared according to the proceduredescribed in our PCT/IB03/01289.

The conversion of compound of the formula (Ia) is carried out withappropriate heterocyclyl or aryl or alkyl sulfonyl chlorides or sulfonicacids such as naphthalene sulfonyl chloride, naphthalene sulfonic acid,phenyl sulfonic acid, phenyl sulfonyl chloride, thiophene sulfonylchloride, thiophene sulfonic acid, propyl sulfonyl chloride, propylsulfonic acid, chloropropyl sulfonyl chloride and the like in thepresence or absence of appropriate solvents like toluene, xylene,tetrahydrofuran, dioxane, chloroform, dichloromethane, dichloroethane,o-dichlorobenzene, acetone, ethyl acetate, acetonitrile,N,N-dimethylformamide, dimethylsulfoxide, pyridine, diphenyl ether,ethanol, methanol, isopropylalcohol, t-butylalcohol, acetic acid,propionic acid etc and the like, or a mixture thereof, or by neatreactions. The reaction may be carried out under acidic conditions usingmineral or organic acids, or basic conditions viz. carbonates,bicarbonates, hydrides, hydroxides, alkyl and alkoxides of alkali metalsand alkaline earth metals. The reaction may be carried out in thepresence of phase transfer catalysts viz. triethylbenzylammoniumchloride, tetrabutylammonium bromide, tetrabutylammoniumhydrogensulphate, tricaprylylmethylammonium chloride (aliquat 336) andthe like. The reaction is usually carried out under cooling to refluxingconditions. The final product is purified by using chromatographictechniques or by recrystallization. The reaction may be carried out fora time period in the range of 2 to 20 hours.

In yet another embodiment of the present invention, there is provided aprocess for the preparation of novel heterocyclic compounds of theformula (I) wherein, R₁, R₂, R₃ and R₄ represent SO₂Cl and all othersymbols are as defined earlier. It comprises reacting the compound offormula (Ic) wherein all the symbols are as defined earlier and any ofR₁, R₂, R₃ and R₄ which represents hydrogen on treatment withchlorosulfonic acid is replaced by —SO₂Cl; this may result in bothpossibilities mono/disubstitution.

The reaction of the compound of formula (Ic) with chlorosulfonic acidmay be carried out in the presence of solvents such as dichloromethane,acetone, tetrahydrofuran, dioxane, ethyl acetate, chloroform and thelike or a mixture thereof or in the absence of solvents. The reactionmay be carried out at a temperature in the range of 0° C. to refluxtemperature for period in the range of 2 to 24 hours.

In yet another embodiment of the present invention, there is provided aprocess for the preparation of novel heterocyclic compounds of theformula (I), wherein R₁, R₂, R₃ or R₄ represent —SO₂NHCH₃, —SO₂NHNH₂ andall the other symbols are as defined earlier, which comprises reactingthe compound of formula (Id), wherein R₁, R₂, R₃ or R₄ represents —SO₂Cland all the other symbols are as defined earlier; with methylamine orappropriate alkylamine or hydrazine hydrate or substituted hydrazine.

The reaction of compound of formula (Id) with alkylamine or theappropriate hydrazine may be carried out in the presence of solventssuch as acetonitrile, dichloromethane, acetone, tetrahydrofuran,dioxane, ethyl acetate, chloroform, water, an alcohol and the like or amixture thereof or in absence of solvents. The reaction may be carriedout at a temperature in the range of 0° C. to reflux temperature forperiod in the range of 2 to 24 hours.

In yet another embodiment of the present invention, there is provided aprocess for the preparation of novel heterocyclic compounds of theformula (I)

wherein R represents substituted or unsubstituted heteroaryl groups andthe other symbols are as defined earlier and they may be prepared byconverting the compound of formula (Ie), wherein all the symbols are asdefined earlier.

The reaction of (Ie) with reagents such as 1-methoxyethylidenemalononitrile, ethyl-2-cyano-3,3-bis(methylthio)acrylate,ethoxymethylene malononitrile, pivaloyl nitrile, acetyl acetone,1-ethoxyethylidene malononitrile etc., in alcoholic solvents such asethanol, methanol, isopropanol, butanol etc., or in chlorinated solventssuch as dichloromethane, dichloroethane, chloroform etc., or hydrocarbonsolvents such as toluene etc., at temperatures ranging from 0 to 200° C.for 0.5 to 24 hours. Some of the heterocyclic compounds thus obtainedare further reacted with acyl or aroyl halides such as substituted orunsubstituted benzoyl chlorides in the presence of bases such astriethyl amine, diisopropylamine etc., in chlorinated solvents such asdichloromethane, dichloroethane, chloroform etc., at temperaturesranging from 0 to 100° C. for 0.5 to 24 hours.

The reactions of (Ie) with 1,3-diketones such as acetylacetone,phenyltrifluoroacetyl acetone etc., was carried out in alcoholicsolvents such as ethanol, methanol etc., at temperatures ranging from 0to 150° C. for 0.5 to 24 hours.

In yet another embodiment of the present invention, there is provided aprocess for the preparation of novel heterocyclic compounds of theformula (I)

wherein R represents

wherein R₅ and R₆ represent independently hydrogen, alkyl, halo, and thelike, and the other symbols are as defined earlier and they may beprepared by converting the compound of formula (Ie), wherein all thesymbols are as defined earlier.

(1e) was treated with corresponding cyclic anhydride and a solvent atroom temperature or higher temperature. Anhydrides are selected frommethylmaleicanhydride, dimethylmaleicanhydride, dichloromaleicanhydride, and the like. Solvent is selected from dimethylformamide,dichloromethane, chloroform, toluene, and the like. Temperature is inthe range of room temperature to 100° C.

The pharmaceutically acceptable salts are prepared by reacting thecompound of formula (I) with 1 to 10 equivalents of a base such assodium hydroxide, sodium methoxide, sodium hydride, potassiumt-butoxide, calcium hydroxide, magnesium hydroxide and the like, insolvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane,isopropanol, ethanol etc. Mixture of solvents may also be used. Organicbases such as diethanolamine, α-phenylethylamine, benzylamine,piperidine, morpholine, pyridine, hydroxyethylpyrrolidine,hydroxyethylpiperidine, choline, guanidine and the like, ammonium orsubstituted ammonium salts, aluminum salts. Amino acids such as glycine,alanine, cystine, cysteine, lysine, arginine, phenylalanine etc may beused for the preparation of amino acid salts. Alternatively, acidaddition salts wherever applicable are prepared by treatment with acidssuch as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, aceticacid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid,ascorbic acid, palmitic acid, succinic acid, benzoic acid,benzenesulfonic acid, tartaric acid, oxalic acid and the like insolvents like ethyl acetate, ether, alcohols, acetone, tetrahydrofuran,dioxane etc. Mixture of solvents may also be used.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms and though one form is named,described, displayed and/or claimed herein, all the forms are intendedto be inherently included in such name, description, display and/orclaim.

The stereoisomers of the compounds forming part of this invention may beprepared by using reactants in their single enantiomeric form, in theprocess wherever possible or by conducting the reaction in the presenceof reagents or catalysts in their single enantiomeric form or byresolving the mixture of stereoisomers by conventional methods. Some ofthe preferred methods include use of microbial resolution, resolving thediastereomeric salts formed with chiral acids such as mandelic acid,camphorsulfonic acid, tartaric acid, lactic acid, and the like whereverapplicable or by using chiral bases such as brucine, cinchona alkaloids,their derivatives and the like.

Prodrugs of the compounds of formula (I) are also contemplated by thisinvention. A prodrug is an active or inactive compound that is modifiedchemically through in-vivo physiological action, such as hydrolysis,metabolism and the like, into a compound of this invention followingadministration of the prodrug to a patient. The suitability andtechniques involved in making and using prodrugs are well known to thoseskilled in the art.

Various polymorphs of the compounds of the general formula (I), formingpart of this invention may be prepared by crystallization of thecompounds of formula (I) under different conditions. For example, usingdifferent commonly used solvents, or their mixtures forrecrystallization; crystallizations at different temperatures; variousmodes of cooling, ranging from very fast to very slow cooling duringcrystallizations. Heating or melting the compounds followed by coolinggradually or immediately, one can also obtain polymorphs. The presenceof polymorphs may be determined by solid probe NMR spectroscopy, IRspectroscopy, differential scanning calorimetry and powder X-raydiffraction or other such techniques.

Pharmaceutically acceptable solvates of the compounds of the formula (I)forming part of this invention may be prepared by conventional methodssuch as dissolving the compounds of the formula (I) in solvents such aswater, methanol, ethanol, mixture of solvents such as acetone:water,dioxane:water, N,N-dimethylformamide:water and the like, preferablywater and recrystallization by using different crystallizationtechniques

The present invention also provides a pharmaceutical composition,containing one or more of the compounds of the general formula (I) asdefined above, their derivatives, analogs, tautomeric forms,stereoisomers, polymorphs, hydrates, metabolites, prodrugs,pharmaceutically acceptable salts, pharmaceutically acceptable solvatesin combination with the usual pharmaceutically employed carriers,diluents and the like, useful for the treatment of inflammation,arthritis, pain, fever, psoriasis, allergic diseases, asthma,inflammatory bowel syndrome, gastro-intestinal ulcers, cardiovasculardisorders including ischemic heart disease, atherosclerosis, cancer,ischemic-induced cell damage, particularly brain damage caused by strokeand other pathological disorders associated with free radicals.

The pharmaceutical composition may be in the forms normally employed,such as tablets, capsules, powders, syrups, solutions, suspensions andthe like, may contain flavorants, sweeteners etc. in suitable solid orliquid carriers or diluents, or in suitable sterile media to forminjectable solutions or suspensions. The compositions may be prepared byprocesses known in the art. The amount of the active ingredient in thecomposition may be less than 70% by weight. Such compositions typicallycontain from 1 to 25%, preferably 1 to 15% by weight of active compound,the remainder of the composition being pharmaceutically acceptablecarriers, diluents, excipients or solvents.

Suitable pharmaceutically acceptable carriers include solid fillers ordiluents and sterile aqueous or organic solutions. The active compoundwill be present in such pharmaceutical compositions in the amountssufficient to provide the desired dosage in the range as describedabove. Thus, for oral administration, the compounds can be combined witha suitable solid or liquid carrier or diluent to form capsules, tablets,powders, syrups, solutions, suspensions and the like. The pharmaceuticalcompositions, may, if desired, contain additional components such asflavorants, sweeteners, excipients and the like. For parenteraladministration, the compounds can be combined with sterile aqueous ororganic media to form injectable solutions or suspensions. For example,solutions in sesame or peanut oil, aqueous propylene glycol and the likecan be used, as well as aqueous solutions of water-solublepharmaceutically-acceptable acid addition salts or alkali or alkalineearth metal salts of the compounds. The injectable solutions prepared inthis manner can then be, administered intravenously, intraperitoneally,subcutaneously, or intramuscularly, with intramuscular administrationbeing preferred in humans.

The pharmaceutical compositions of the invention are effective inlowering TNF-α, IL-β, levels, COX-1, and COX-2 activity without causingulcers. The pharmaceutical compositions of the invention are thuseffective for treating rheumatoid arthritis, osteoarthritis, rheumatoidspondylitis, gouty arthritis, inflammatory bowel disease, psoriasis,Crohn's disease, allergic rhinitis, ulcerative colitis, bone resorptiondiseases and osteoporosis. The pharmaceutical compositions of theinvention are also effective in the treatment of ischemic heart disease,ischemic-induced cell damage, ischemia reperfusion injury,atherosclerosis, brain trauma, multiple sclerosis, sepsis, septic shock,toxic shock syndrome, fever and myalgias due to infection. Thepharmaceutical compositions of the present invention are also effectivein treating cancer, acute and chronic myelogenous leukemia, multiplemyeloma, and pancreatic β cell destruction. Furthermore, pharmaceuticalcompositions of the present invention are useful for the treatment ofdisorders, which includes adult respiratory distress syndrome (ARDS),anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia,type I and type II diabetes.

Generally, the effective dose for treating a particular condition in apatient may be readily determined and adjusted by the physician duringtreatment to alleviate the symptoms or indications of the condition ordisease. Generally, a daily dose of active compound in the range ofabout 0.01 to 1000 mg/kg of body weight is appropriate foradministration to obtain effective results. The daily dose may beadministered in a single dose or divided into several doses. In somecases, depending upon the individual response, it may be necessary todeviate upwards or downwards from the initially prescribed daily dose.Typical pharmaceutical preparations normally contain from about 0.2 toabout 500 mg of active compound of formula I and/or its pharmaceuticallyactive salts or solvates per dose.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are given at the same time or differenttimes, or the therapeutic agents can be given as a single composition.

The term “therapeutically effective amount” or “effective amount” refersto that amount of a compound or mixture of compounds of Formula I thatis sufficient to effect treatment, as defined below, when administeredalone or in combination with other therapies to a mammal in need of suchtreatment. More specifically, it is that amount that is sufficient tolower the cytokines such as TNF-α, IL-β, IL-6, and to treat autoimmunediseases, inflammation, immunological diseases and cancer.

The term “animal” as used herein is meant to include all mammals and inparticular humans. Such animals are also referred to herein as subjectsor patients in need of treatment. The therapeutically effective amountwill vary depending upon the subject and disease condition beingtreated, the weight and age of the subject, the severity of the diseasecondition, the particular compound of Formula I chosen, the dosingregimen to be followed, timing of administration, the manner ofadministration and the like, all of which can readily be determined byone of ordinary skill in the art.

The term “treatment” or “treating” means any treatment of a disease in amammal, including:

a) Preventing the disease, that is, causing the clinical symptoms of thedisease not to develop;b) Inhibiting the disease, that is, slowing or arresting the developmentof clinical symptoms; and/orc) Relieving the disease, that is, causing the regression of clinicalsymptoms.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, make various changes andmodifications of the invention to adapt it to various usages andconditions.

In yet another embodiment of the present invention, there is providedbiological activity data in tables I to XV for the selected compounds invarious in vitro and in vivo methods involving various disease modelslike Cancer, Psoriasis, Intestinal bowel disease, Arthritis, TNF alphaand PDE4 mediated diseases such as asthma and COPD. Further clinicalstudies of selected compounds are in progress.

The present invention is provided by the examples given below, which areprovided by the way of illustration only and should not be considered tolimit the scope of the invention. Variation and changes, which areobvious to one skilled in the art, are intended to be within the scopeand nature of the invention, which are defined in the appended claims.

Preparation 1 Preparation of6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-amine

Ammonia gas was purged through a solution of4-chloro-6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidine(5.5 g, 13.33 mmol, prepared according to the procedure described inPCT/IB03/02879) in THF (500 ml), continuously for 30 hours understirring at 0-10° C. After completion of the reaction the THF wasdistilled completely in-vacuo, water (100 ml) was added and the reactionmixture was extracted with ethyl acetate (3×200 ml). The combinedorganic layer was washed with brine (150 ml), dried over anhydroussodium sulphate and concentrated under, reduced pressure to give6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-amine(3.6 g, yield 87.79%).

The following compounds were prepared according to the above procedure

Ex. Structure Analytical Data 1

¹H-NMR (DMSO-d₆) δ: 1.86 (s, 3H), 3.16 (s, 3H), 6.77 (bs, 1H, D₂Oexchangeable), 7.38-7.55 (m, 2H), 7.59- 7.73 (m, 2H), 7.75-7.86 (m, 5H),12.04 (s, 1H, D₂O exchangeable). IR (KBr) cm⁻¹: 3472, 3342, 3204, 1715and 1630; MS m/z: 515.1 (M⁺ + 1). 2

¹H-NMR (DMSO-d₆) δ: 2.04-2.05 (d, 3H), 3.16 (s, 3H), 6.66 (bs, D₂Oexchangeable), 7.29-7.30 (m, 1H, D₂O exchangeable), 7.42-7.45 (m, 3H),7.61- 7.7 (m, 2H), 7.72-7.77 (m, 3H), 8.11 (bs, 1H, D₂O exchangeable).IR (KBr) cm⁻¹: 3423, 3339, 3242, 1639 and 1579; MS m/z: 487.2 (M⁺ + 1).

Example 3 Synthesis of4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonylchloride

To a solution of chlorosulphonic acid (605 mmol, 40.4 ml) was added4-chloro-6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidine(5.0 g, 12.1 mmol, prepared according to the procedure described inPCT/IB03/02879) slowly under continuous stirring at 0° C. until thecompletion of the addition. The reaction mixture was further stirred at32° C. until TLC confirmed the completion. Subsequently the resultingreaction mass was poured slowly under vigorous stirring onto crushed iceand the solid obtained was filtered, washed thoroughly with water (100ml) and extracted with ethyl acetate (3×200 ml). The combined organiclayer was washed with brine (150 ml), dried over anhydrous sodiumsulphate and concentrated under reduced pressure to afford4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonylchloride (2.75 g, yield 65.59%, purity by HPLC 98.17%); m.p: 207-210° C.¹H-NMR (400 MHz, CDCl₃) δ: 3.01 (s, 3H), 7.511-7.515 (d, 2H), 7.53-7.67(m, 1H), 7.72-7.76 (t, 1H), 7.86-7.89 (m, 3H), 8.11-8.13 (d, 1H). IR(KBr) cm⁻¹: 1557, 1524; MS m/z: 511.6 (M⁺).

Example 4 Synthesis of4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}-N-methylbenzenesulfonamide

To a solution of4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonylchloride (0.5 g, 0.98 mmol, prepared according to the proceduredescribed for example 3) in dichloromethane (5 ml) was added methylaminesolution (0.08 ml, 0.98 mmol, 40% aqueous solution) under stirring at0-10° C. After 15 minutes of the stirring, TLC confirmed the completionof the reaction. Subsequently the solvent was distilled off underreduced pressure and the solid thus obtained was filtered, washedthoroughly with cold water to yield the title compound (0.446 g, yield90.1%, purity by HPLC 98.1%). m.p: 226-230° C. ¹H-NMR (400 MHz, DMSO-d₆)δ: 2.09-2.10 (d, 3H), 3.1 (s, 3H), 7.43-7.44 (m, 1H, D₂O exchangeable),7.54-7.56 (d, 2H), 7.69-7.81 (m, 4H), 7.86-7.88 (d, 2H). IR (KBr) cm⁻¹:3335, 1562 and 1530; MS m/z: 506.1 (M⁺+1).

The Following Compounds were Prepared According to the ProcedureDescribed for Example 4

Ex. Structure Analytical Data 5.

¹H-NMR (DMSO-d₆) δ: 2.03-2.04 (d, 3H), 2.85-2.87 (d, 3H), 3.15 (s, 3H),7.12 (s, 1H, D₂O exchangeable), 7.13-7.31 (m, 1H, D₂O exchangeable),7.32-7.44 (m, 3H), 7.64-7.4 (m, 2H), 7.75-7.77 (m, 3H). IR (KBr) cm⁻¹:3372, 3326, 1589 and 1551; MS m/z: 501.2 (M⁺ + 1). 6

¹H-NMR (DMSO-d₆) δ: 1.18 (s, 3H), 2.85- 2.86 (d, 3H), 3.16 (s, 3H),7.08-7.09 (m, 1H, D₂O exchangeable), 7.4-7.42 (m, 2H), 7.55-7.57 (m,1H), 7.62-7.66 (m, 1H), 7.72-7.76 (3H), 7.87-7.89 (d, 1H), 12.04 (s, 1H,D₂O exchangeable). IR (KBr) cm⁻¹: 3413, 3151, 1719 and 1588; MS m/z: 529(M⁺ + 1).

Example 7 Synthesis of4-{4-hydrazino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonohydrazide

To a suspension of 4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonyl chloride (1 g, 1.9 mmol, preparedaccording to the procedure described for Example 3) in ethanol (10 ml)was added hydrazine hydrate (0.195 g, 3.9 mmol), at 0-10° C. understirring. The stirring was continued at the same temperature for 3 hoursuntil TLC using ethyl acetate and hexane as solvent system confirmed thecompletion of the reaction. The solid that reappeared was filtered andwashed with ethanol (5 ml) and finally with hexane (10 ml) to afford thedesired compound (0.9 g, yield 91.56%, purity by HPLC 94.49%); m.p.203-206° C. ¹H-NMR (DMSO-d₆) δ: 3.17 (s, 3H), 4.0 (s, 2H, D₂Oexchangeable), 7.44-7.46 (d, 3H), 7.59-7.64 (m, 1H), 7.76-7.77 (d, 3H),8.33s, 1H), 8.44 (s, 1H, D₂O exchangeable). IR (KBr) cm⁻¹: 3353, 1581,1567; MS m/z: 503.1 (M⁺+1).

The following compounds were prepared according to the proceduredescribed for example 7

Ex. Structure Analytical Data 8

¹H-NMR (DMSO-d₆) δ: 4.04 (s, 2H, D₂O exchangeable), 4.37 (s, 2H, D₂Oexchangeable), 7.05-7.1 (m, 2H), 7.18- 7.27 (m, 3H), 7.41-7.43 (m, 2H),7.59- 7.63 (m, 1H), 8.30-8.35 (m, 1H, D₂O exchangeable), 8.77 (bs, 1H,D₂O exchangeable); MS m/z: 443 (M⁺ + 1) 9

¹H-NMR (DMSO-d₆) δ: 1.87 (s, 3H), 3.16 (s, 3H), 4.65 (bs, 2H, D₂Oexchangeable), 7.4-7.5 (m, 3H), 7.57-7.61 (m, 1H), 7.71-7.80 (m, 3H),7.84-7.86 (d, 1H), 8.52 (s, 1H), 12.05 (s, 1H, D₂O exchangeable). IR(KBr) cm⁻¹: 3388, 3209, 1734, 1583; MS m/z: 530 (M⁺ + 1). 10

¹H-NMR (DMSO-d₆) δ: 2.06-2.07 (d, 3H), 3.15-3.17 (s, 3H), 4.61 (bs, 2H,D₂O exchangeable), 7.28-7.32 (m, 1H), 7.42-7.44 (m, 3H), 7.55-7.65 (m,2H), 7.7-7.79 (m, 3H), 8.53 (s, 1H, D₂O exchangeable); MS m/z: 502.2(M⁺ + 1). 11

¹H-NMR (CDCl₃) δ: 4.09 (bs, 2H, D₂O exchangeable), 6.27 (s, 1H, D₂Oexchangeable), 7.16-7.19 (m, 3H), 7.41- 7.72 (m, 3H), 7.25-7.74 (m, 1H),8.47- 8.5 (m, 2H); MS m/z: 332 (M⁺ + 1). 12

¹H-NMR (CDCl₃) δ: 4.08 (bs, 2H, D₂O exchangeable), 6.28 (s, 1H, D₂Oexchangeable), 7.13-7.18 (m, 2H), 7.21- 7.22 (m, 2H), 8.46 (s, 3H),8.46-8.47 (m, 2H); MS m/z: 332 (M⁺ + 1). 13

¹H-NMR (CDCl₃) δ: 4.09 (bs, 2H, D₂O exchangeable), 6.24 (s, 1H, D₂Oexchangeable), 7.14-7.16 (m, 4H), 7.18- 7.20 (m, 2H), 8.49-8.5 (d, 2H);MS m/z: 350.2 (M⁺ + 1).

Example 14 Synthesis of2,2,2-trifluoro-N′-[5-(4-fluorophenyl)-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidin-4-yl]acetohydrazide

To a solution of5-(4-fluorophenyl)-4-hydrazino-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidine(0.5 g, 1.43 mmol, example 13, prepared according to the proceduredescribed for example 7) in dichloromethane (10 ml) was addedtrifluoroacetic anhydride (0.22 ml, 1.57 mmol) under stirring at −40° C.The stirring was continued at the same temperature for 30 minutes, untilTLC using ethyl acetate and hexane (3:7) as solvent system confirmed thecompletion of the reaction. Subsequently the reaction mixture was pouredonto ice and extracted with ethyl acetate (50 ml), dried over anhydroussodium sulphate and evaporated to afford the desired compound (0.34 g,yield 53.3%, purity by HPLC 97%); m.p. 240-242° C. ¹H-NMR (DMSO-d₆) δ:7.17-7.35 (m, 6H), 8.49-8.50 (d, 2H), 9.3 (s, 1H), 11.7 (s, 1H, D₂Oexchangeable). IR (KBr) cm⁻¹: 3678, 3395, 3208 and 1742; MS m/z: 446.1(M⁺+1).

Following compounds were prepared according to the procedure describedfor example 14

Ex. Structure Analytical data 15

¹H-NMR (CDCl₃) δ: 2.12 (s, 3H), 7.21- 7.22 (m, 2H), 7.46-7.47 (m, 3H),8.0 (s, 1H), 8.48-8.49 (d, 2H); IR (KBr) cm⁻¹: 3257, 1694, 1577 and1571; MS m/z: 374 (M⁺ + 1). 16

¹H-NMR (DMSO-d₆) δ: 7.21-7.22 (m, 2H), 7.7.27-7.29 (m, 2H), 7.42- 7.43(d, 2H), 9.26 (s, 1H, D₂O exchangeable), 10.8 (s, 1H, D₂O exchangeable);MS m/z: 428 (M⁺ + 1).

Example 17 Synthesis ofN-[(4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}phenyl)sulfonyl]acetamide

A solution of4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide(0.5 g, 1.01 mmol, prepared according to the procedure described inPCT/IB03/02879), DMAP (0.01 g) and acetyl chloride (0.5 g, 6.36 mmol)were stirred at 30° C. TLC confirmed the completion of the reactionafter 4 hours of stirring under the same conditions. Subsequently theresulting mass was poured onto the ice and the procedure described forexample 14 was followed to afford the title compound (0.252 g, 46.41%,purity by HPLC 98.82%); m.p.: 230-235° C. ¹H-NMR (DMSO-d₆) δ: 1.87 (s,3H), 3.17 (s, 3H), 7.51-7.53 (m, 2H), 7.66-7.67 (m, 2H), 7.8-7.82 (d,2H), 7.9 (s, 1H), 7.99 (s, 1H), 12.14 (s, 1H, D₂O exchangeable); IR(KBr) cm⁻¹: 3150, 1720 and 1525; MS m/z: 533.7 (M⁺).

Example 18 Synthesis of6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-ylnapthalenesulfonate

To a solution of6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-ol(0.1 g, 0.25 mmol, prepared according to the procedure described inPCT/IB03/01289) in dichloromethane (10 ml) was addednaphthalene-1-sulfonyl chloride (0.086 g, 0.37 mmol) in dichloromethane(4 ml) at 0° C. and the mixture was stirred for 10 minutes. Subsequentlypyridine (0.04 ml, 0.5 mmol) was added under stirring and the stirringwas continued further for 6 hours at 37° C. Dichloromethane was removedunder vacuo and the resultant mixture was diluted withwater:ethyl:acetate (1:1, 100 ml) and then extracted with ethyl acetate(3×25 ml). The organic layer was washed with brine (100 ml), dried overanhydrous sodium sulphate and evaporated to afford the title compound(0.096 g, yield 67%); m.p. 204-206° C. ¹H-NMR (CDCl₃) δ: 2.99 (s, 3H),7.12-7.14 (d, 2H), 7.26-7.29 (dd, 3H), 7.37-7.39 (m, 2H), 7.48-7.50 (m,2H), 7.61-7.64 (m, 3H), 7.77-7.79 (d, 2H), 7.84-7.86 (d, 2H), 7.94-7.96(d, 2H); MS m/z: 585.1 (M⁺+1).

The Following Compounds were Prepared According to the ProcedureDescribed for Example 18

Ex. Structure Analytical Data 19

¹H-NMR (CDCl₃) δ: 2.42-2.45 (m, 2H), 2.99 (s, 3H), 3.68-3.71 (t, 2H),3.97-4.01 (t, 2H), 7.19-7.86 (m, 9H); MS m/z: 535.5 (M⁺ + 1). 20

¹H-NMR (CDCl₃) δ: 3.02 (s, 3H), 7.18-7.20 (d, 2H), 7.21-7.26 (dd, 3H),7.41-7.43 (m, 2H), 7.55-7.57 (dd, 1H), 7.76-7.81 (dd, 2H), 7.97- 8.44(m, 3H); MS m/z: 603.54 (M⁺ + 1). 21

¹H-NMR (CDCl₃) δ: 3.02 (s, 3H), 7.17-7.20 (d, 2H), 7.21-7.26 (dd, 3H),7.40-7.43 (m, 2H), 7.81-7.83 (m, 4H), 7.84-7.86 (dd, 1H), 8.41- 8.43(dd, 1H); MS m/z: 603.51 (M⁺ + 1). 22

¹H-NMR (CDCl₃) δ: 2.47 (s, 3H), 3.02 (s, 3H), 7.17-7.20 (d, 2H), 7.21-7.26 (dd, 3H), 7.40-7.43 (m, 2H), 7.81-7.83 (m, 4H), 7.84-7.86 (dd, 1H),8.41-8.43 (dd, 1H); MS m/z: 603.51 (M⁺ + 1). 23

¹H-NMR (CDCl₃) δ: 3.02 (s, 3H), 7.18-7.20 (d, 2H), 7.21-7.26 (dd, 3H),7.41-7.43 (m, 2H), 7.55-7.57 (dd, 1H), 7.76-7.81 (dd, 2H), 7.97- 8.44(m, 3H); MS m/z: 603.54 (M⁺ + 1). 24

¹H-NMR (CDCl₃) δ: 3.00 (s, 3H), 7.17-7.20 (d, 2H), 7.21-7.26 (dd, 3H),7.40-7.43 (m, 2H), 7.81-7.80 (m, 4H), 7.84-7.87 (dd, 1H), 8.40- 8.42(dd, 1H); MS m/z: 603.51 (M⁺ + 1). 25

¹H-NMR (CDCl₃) δ: 3.03 (s, 3H), 7.17-7.20 (d, 2H), 7.21-7.26 (dd, 3H),7.81-7.83 (m, 4H), 7.84-7.86 (dd, 1H), 8.41-8.43 (dd, 1H); MS m/z:603.51 (M⁺ + 1). 26

¹H-NMR (CDCl₃) δ: 3.01 (s, 3H), 7.17-7.20 (d, 2H), 7.21-7.24 (dd, 3H),7.40-7.43 (m, 2H), 7.81-7.83 (m, 4H), 7.84-7.86 (dd, 1H), 8.41- 8.43(dd, 1H); MS m/z: 603.51 (M⁺ + 1). 27

¹H-NMR (CDCl₃) δ: 3.01 (s, 3H), 7.17-7.20 (d, 2H), 7.21-7.24 (dd, 3H),7.40-7.43 (m, 2H), 7.81-7.83 (m, 4H), 7.84-7.86 (dd, 1H), 8.41- 8.43(dd, 1H); MS m/z: 603.51 (M⁺ + 1). 28

¹H-NMR (CDCl₃) δ: 0.88-0.89 (m, 2H), 1.25-1.28 (t, 2H), 1.33-1.38 (t,2H), 2.85 (s, 6H), 2.97 (s, 3H), 7.04-7.74 (m, 9H); MS m/z: 544.59 (M⁺ +1).

Example 29 Synthesis of6-[4-(methylsulfonyl)phenyl]-5-phenyl-4-(N-benzyl-piperazin-1-yl)-2-(trifluoromethyl)pyrimidine

To a suspension of Pd₂(dba)₃ (0.443 g, 0.484 mmol) in toluene (50 ml)was added racemic-2,2′-bis(diphenyl phosphino)-1,1′-dinaphthyl (0.151 g,0.242 mmol) at 37° C. under stirring. After 10 minutes of stirring theresulting solution was added to a suspension of N-benzyl piperazine(2.51 ml, 14.55 mmol),4-chloro-6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidine(5 g, 12.12 mmol, prepared according to the procedure described inPCT/IB03/02879) and cesium carbonate (5.53 g, 16.9 mmol) in toluene (80ml) under stirring. Subsequently the reaction mixture was refluxed for 6hours and filtered. The solid obtained was washed thoroughly with ethylacetate and the resultant organic layer was washed successively withwater (3×100 ml), brine (200 ml) then dried over anhydrous sodiumsulphate and evaporated to afford the title compound (5.5 g, yield82.21%).

Preparation 2 Method A Preparation of6-[4-(methylsulfonyl)phenyl]-5-phenyl-4-piperazin-1-yl-2-(trifluoromethyl)pyrimidine

To a solution of6-[4-(methylsulfonyl)phenyl]-5-phenyl-4-(N-benzyl-piperazin-1-yl)-2-(trifluoromethyl)pyrimidine(5 g, 9 mmol) in dry dichloromethane (20 ml) was added diisopropylethylamine (2.5 ml, 18 mmol) under stirring at 0° C. 1-chloro-ethylchloroformate (1.35 ml, 13.5 mmol) was later added to the above, understirring and the stirring was further continued at 37° C. for 5 hours.Subsequently dichloromethane was evaporated upto dryness and methanol(20 ml) was added dropwise to the resulting mass, which was refluxed for3 hours at 60° C. The reaction mixture was poured onto ice and filtered;the solid obtained was washed with hexane (100 ml) and diisopropyl ether(50 ml), to give the title compound (4 g, yield 95.9%).

Method B

Piperazine (4.12 g, 47.8 mmol) was added to a solution of4-chloro-5,6-diphenyl-2-trifluoromethylpyrimidine (4.0 g, 11.95 mmol)prepared according to the procedure described in the PCT/IB03/02879 inacetonitrile (30 ml) under stirring at 37° C. After 2 hours when TLCconfirmed the completion of the reaction, the reaction mixture waspoured onto ice and extracted with ethyl acetate (250 ml). The organiclayer was dried over anhydrous sodium sulphate and evaporated to affordthe title compound (3.5 g, yield 76.25%, purity by HPLC 100%); m.p:160-162° C. ¹H-NMR (DMSO-d₆) δ: 2.5 (s, 4H), 3.16 (t, 4H), 7.07-7.08 (m,2H), 7.17-7.31 (m, 9H, 1H, D₂O exchangeable); IR cm⁻¹ (KBr): 3304, 3058,and 1559; MS m/z: 385.2 (M⁺+1).

The Following Compounds were Prepared According to the ProcedureDescribed for the Preparation 2

Ex. Structure Analytical Data 30

¹H-NMR (DMSO-d₆) δ: 2.98 (s, 4H), 3.35-3.42 (m, 4H), 7.36-7.38 (m, 1H),7.44-7.48 (m, 2H), 7.52-7.56 (m, 1H), 7.77-7.79 (m, 2H), 9.24 (s, 2H,D₂O exchangeable); MS m/z: 482.1 (M⁺ + 1). 31

¹H-NMR (DMSO-d₆) δ: 3.01 (s, 4H), 3.42 (s, 4H), 7.1-7.11 (m, 2H), 7.26-7.32 (m, 3H), 7.38-7.41 (m, 2H), 7.75-7.77 (s, 3H), 9.0 (s, 2H, D₂Oexchangeable); MS m/z: 482.1 (M⁺ + 1). 32

¹H-NMR (DMSO-d₆) δ: 2.09 (s, 4H), 2.7 (s, 3H), 3.15 (s, 3H), 3.22-3.32(d, 4H), 7.35-7.37 (m, 2H), 7.51- 7.55 (m, 3H), 7.62-7.64 (m, 1H),7.70-7.79 (m, 2H); MS m/z: 556.1 (M⁺ + 1). 33

¹H-NMR (CDCl₃) δ: 2.15 (s, 3H), 3.02 (s, 4H), 3.47 (s, 4H), 4.5 (s, 1H,D₂O exchangeable), 7.26 (s, 2H), 7.32- 7.36 (m, 3H), 7.47-7.51 (m, 2H),7.77-7.79 (m, 4H); MS m/z: 542.1 (M⁺ + 1). 34

¹H-NMR (CDCl₃) δ: 2.4-2.41 (d, 3H), 3.0 (s, 3H), 3.34-3.37 (m, 4H),3.58-3.6 (m, 4H), 4.1-4.3 (m, 1H, D₂O exchangeable), 7.26-7.31 (m, 2H),7.46 (s, 2H), 7.54-7.58 (m, 1H), 7.78-7.8 (m, 3H); IR cm⁻¹ (KBr): 3205,2886, 2856, 1693 and 1557; MS m/z: 557.1 (M⁺). 35

¹H-NMR (CDCl₃) δ: 1.19-1.22 (m, 4H), 1.56-1.62 (m, 2H), 2.39-2.41 (d,3H), 3.0 (s, 3H), 3.29-3.31 (m, 4H), 4.13-4.15 (m, 1H, D₂Oexchangeable), 7.26-7.29 (m, 2H), 7.442-7.446 (m, 2H), 7.51-7.54 (m,1H), 7.74-7.78 (m, 3H); IR cm⁻¹ (KBr): 3280, 2938, 2851, 1561 and 1525;MS m/z: 555 (M⁺).

Preparation 3 Preparation of6-[4-(methylsulfonyl)phenyl]-5-phenyl-4-[4-(2-thienylcarbonyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidine

To a solution of6-[4-(methylsulfonyl)phenyl]-5-phenyl-4-piperazin-1-yl-2-(trifluoromethyl)pyrimidine(0.2 g, 0.43 mmol, prepared according to the procedure described inpreparation 2) in DMF (20 ml) was added thiophene-2-carboxylic acid(0.149 g, 0.78 mmol) under stirring at 37° C. and then after 10 minutesEDCI (0.149 g, 0.78 mmol), and HOBt (0.023 g, 0.173 mmol) were added.Further TEA (0.179 ml, 2.9 mmol) was added to the resultant clearsolution and it was stirred for 18 hours. Subsequently the reactionmixture was diluted with ethyl acetate (50 ml) and the organic layer waswashed successively with water, 10% sodium bi carbonate solution (100ml) and brine (100 ml) respectively and dried over anhydrous sodiumsulphate. Evaporation of the solvent and purification by columnchromatography (0.4% MeOH: DCM) gave the title compound (0.12 g, yield48.6%); m.p. 189-194° C. ¹H-NMR (CDCl₃) δ: 2.98 (s, 3H), 3.4-3.41 (t,4H), 3.66-3.68 (t, 4H), 7.02-7.77 (m, 12H); MS m/z: 573.2 (M⁺+1).

The Following Compounds were Prepared According to the ProcedureDescribed for the Preparation 3

Ex. Structure Analytical data 36

¹H-NMR (CDCl₃) δ: 2.67 (s, 3H), 2.98 (s, 3H), 3.43-3.45 (t, 4H),3.63-3.64 (t, 2H), 3.68-3.7 (t, 2H), 7.11-8.84 (m, 11H); MS m/z: 583.2(M⁺ + 1). 37

¹H-NMR (CDCl₃) δ: 2.98 (s, 3H), 3.37- 3.39 (t, 4H), 3.63-3.67 (t, 4H),3.75 (s, 3H), 6.95-7.77 (m, 11H); MS m/z: 570.63 (M⁺ + 1). 38

¹H-NMR (CDCl₃) δ: 2.99 (s, 3H), 3.49- 3.51 (t, 4H), 3.82-3.83 (t, 4H),7.13- 7.18 (m, 3H), 7.26-7.34 (m, 6H), 7.76-7.78 (dd, 2H); MS m/z: 602.1(M⁺ + 1) . 39

¹H-NMR (CDCl₃) δ: 2.43-2.44 (d, 3H), 3.01 (s, 3H), 3.47 (s, 4H), 3.71-3.85 (d, 4H), 4.39 (s, 1H, D₂O exchangeable), 7.19 (s, 1H), 7.26-7.33(m, 3H), 7.43-7.45 (m, 1H), 7.54- 7.59 (m, 2H), 7.79-7.81 (d, 3H); MSm/z: 695.1 (M⁺ + 1). 40

¹H-NMR (DMSO-d₆) δ: 3.35 (s, 4H), 3.54-3.67 (d, 4H), 7.06-7.16 (m, 5H),7.23-7.24 (d, 1H), 7.35-7.73 (m, 3H), 7.74-7.78 (m, 3H); MS m/z: 621.2(M⁺ + 1). 41

¹H-NMR (DMSO-d₆) δ: 3.36 (s, 4H), 3.33-3.67 (d, 4H), 7.13-7.21 (m, 4H),7.26-7.4 (m, 4H), 7.72-7.74 (d, 4H); MS m/z: 621.2 (M⁺ + 1). 42

¹H-NMR (CDCl₃) δ: 2.99 (s, 3H), 3.48- 3.51 (t, 4H), 3.87-3.88 (t, 4H),7.12- 7.13 (m, 1H), 7.14-7.15 (t, 2H), 7.26- 7.28 (m, 5H), 7.76-7.78(dd, 2H); MS m/z: 602.3 (M⁺ + 1). 43

¹H-NMR (CDCl₃) δ: 3.37-3.45 (d, 4H), 3.63-3.81 (d, 4H), 7.13-7.26 (m,8H), 7.30-7.33 (m, 4H); MS m/z: 524.1 (M⁺ + 1). 44

¹H-NMR (CDCl₃) δ: 3.43-3.51 (d, 4H), 3.68-3.87 (d, 4H), 7.02-7.15 (m,7H), 7.34-7.35 (d, 1H), 8.49-8.5 (d, 2H); IR (KBr) cm⁻¹: 3428 and 1633;MS m/z: 543.1 (M⁺ + 1).

Example 45 Synthesis of6-[4-(methylsulfonyl)phenyl]-5-phenyl-4-[4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidine

To a solution of6-[4-(methylsulfonyl)phenyl]-5-phenyl-4-piperazin-1-yl-2-(trifluoromethyl)pyrimidine(0.2 g, 0.43 mmol, prepared according to the procedure described inpreparation 2) in dichloroethane (25 ml) was addedthiazole-2-carboxaldehyde (0.144 g, 1.3 mmol) under stirring at 37° C.After five minutes, sodium triacetoxy borohydride (0.364 g, 1.72 mmol)was added to reaction mixture and then after 10 minutes, acetic acid(0.1 ml) was added to it. The reaction mixture was stirred for 36 hoursunder the same conditions. Subsequently the reaction mixture was treatedwith ethyl acetate:water (1:1, 100 ml) and extracted with ethyl acetate(3×50 ml). The organic layer was washed with brine (100 ml) and driedover anhydrous sodium sulphate. The solid obtained upon evaporation waspurified by column chromatography using methanol: dichloromethane(0.5:99.5) as an eluent to afford the title compound (0.11 g, yield45.6%). ¹H-NMR (CDCl₃) δ: 0.88-0.89 (m, 2H), 1.25-1.28 (t, 2H),1.33-1.38 (t, 2H), 2.85 (s, 6H), 2.97 (s, 3H), 7.04-7.74 (m, 9H); MSm/z: 544.59 (M⁺+1).

The following compounds were prepared according to the proceduredescribed for example 45

Ex. Structure Analytical Data 46

¹H-NMR (CDCl₃) δ: 2.50-2.53 (t, 4H), 2.98 (s, 3H), 3.44-3.46 (t, 4H),3.88 (s, 2H), 7.14-7.78 (m, 13H); MS m/z: 554.3 (M⁺ + 1). m.p.: 228-232°C. 47

¹H-NMR (CDCl₃) δ: 2.51-2.52 (t, 4H), 2.99 (s, 3H), 3.44-3.46 (t, 4H),3.88 (s, 2H), 7.10-7.81 (m, 11H); MS m/z: 604.7 (M⁺ + 1). m.p,: 168-174°C.

Example 48 Synthesis of4,5-diphenyl-6-(4-pyridin-2-yl-piperazin-1-yl)-2-(trifluoromethyl)pyrimidine

To a solution of 4-chloro-5,6-diphenyl-2-(trifluoromethyl)pyrimidine(0.5 g, 1.49 mmol, prepared according to the procedure described inPCT/IB03/02879) in DMF (5 ml) was added 1-pyridin-2-yl piperazine (0.107g, 0.66 mmol) and anhydrous potassium carbonate (0.2 g) under stirringat 28° C. The reaction mixture was stirred for 4 hours and when TLCconfirmed the completion, it was poured onto ice. The solid thusobtained was filtered and washed with water (20 ml). The above solid wasthen dissolved in dichloromethane (50 ml) and dried over anhydroussodium sulphate. Evaporation of the solvent afforded the title compound(0.48 g, yield 69.66%, purity by HPLC 99.8%). m.p. 165-167° C. ¹H-NMR(CDCl₃) δ: 3.43 (s, 8H), 6.58-6.64 (m, 2H), 7.14-7.21 (m, 7H), 7.26-7.29(m, 3H), 7.45-7.49 (t, 1H), 8.14-8.15 (d, 1H); IR cm⁻¹ (KBr): 3436,2839, 1591 and 1557; MS m/z: 462.1 (M⁺+1).

The Following Compound was Prepared as Per the Above-Mentioned Procedure

Ex. Structure Analytical Data 49

¹H-NMR (DMSO-d₆) δ: 3.18-3.21 (d, 3H), 3.17-3.4 (d, 8H), 6.63-6.66 (t,1H), 6.76-6.78 (d, 1H), 7.27-7.28 (d, 2H), 7.35-7.37 (d, 5H), 7.49-7.53(t, 1H), 7.76-7.78 (d, 2H), 8.07-8.08 (d, 1H), MS m/z: 540.4 (M⁺ + 1).m.p.: 229-233° C.

Preparation 4 Preparation of3-[4-(4-fluorophenyl)-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamidehydrochloride [Hydrochloride of the Example-50] and4-[4-(4-fluorophenyl)-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamidehydrochloride [Example-30] Step 1 Preparation of3-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonylchloride and4-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonylchloride

4-Chloro-6-(4-fluorophenyl)-5-phenyl-2-(trifluoromethyl)pyrimidine (30g, 0.085 mol) was added to cold chlorosulfonic acid (200 ml, 3.0 mol)and the reaction mixture was stirred for 48 hours at room temperature.Subsequently it was poured into crushed ice (˜3 kg) and was extractedwith dichloromethane (1000 mL). The organic layer was washed with sodiumbicarbonate (7%, 1000 mL) and with brine solution (500 mL). The crudematerial obtained after evaporation was recrystallised from hexane-EtOActo obtain the pure para and meta substituted sulphonyl chlorides.However, the crude product containing mixture of meta and para isomerswas used as such in the examples mentioned below unless otherwisementioned.

3-[4-Chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonylchloride: ¹H-NMR (CDCl₃) δ: 6.97-7.01 (m, 2H), 7.32-7.36 (m,2H), 7.63-7.65 (d, 1H), 7.71-7.74 (t, 1H), 7.90-7.91 (s, 1H), 8.10-8.12(d, 1H).

4-[4-Chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonyl chloride: ¹H-NMR (CDCl₃) δ: 6.97-7.01 (m, 2H), 7.34-7.38 (m,2H), 7.50-7.53 (d, 2H), 8.11-8.13 (d, 2H).

Step 2a Preparation of3-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide

The sulphonyl chloride group is converted into the sulphonamido group bytreatment with ammonia gas under cold conditions (0-5° C.) by dissolvingthe substance in dichloromethane. Subsequently the reaction mixture waswashed with water (100 mL) and then with brine solution; evaporation ofthe solvent furnished the title compound. ¹H-NMR (DMSO-d₆) δ: 7.14-7.18(m, 2H), 7.38-7.42 (m, 2H), 7.48 (brs, 2H, D₂O exchangeable), 7.56 (d,1H), 7.62-7.66 (t, 1H), 7.86 (s, 1H), 7.88 (d, 1H); MS m/z: 433 (M⁺+1).

Step 2b Preparation of4-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide

Similarly 4-[6-chloro-5-phenyl-2-(trifluoromethyl)pyrimdin-4-yl]benzenesulfonamide was prepared from4-chloro-5,6-diphenyl-2-(trifluoromethyl)pyrimidine which in turn wasprepared according to the procedure described in PCT/IB03/02879). ¹H-NMR(DMSO-d₆) δ: 7.16-7.21 (m, 2H), 7.38-7.41 (m, 2H), 7.48 (brs, 2H, D₂Oexchangeable), 7.57 (d, 2H), 7.86 (d, 2H); MS m/z: 432 (M⁺).

Example 50 Synthesis of,3-[4-(4-fluorophenyl)-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide

The solution of3-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide(0.1 g, 0.24 mmol, prepared according to the procedure described abovein preparation 4, Step 2a), in acetonitrile (2 ml) was treated withpiperazine (0.104 g, 1.203 mmol) and the reaction mixture was stirredovernight at room temperature. Subsequently the reaction mixture waspoured into ice-cold water and was extracted with ethylacetate (25 ml).The organic layer was washed with water, brine solution and thenevaporated to obtain the title compound. ¹H-NMR (DMSO-d₆) δ: 2.58 (s,4H), 3.19 (s, 4H), 7.03-7.14 (m, 4H), 7.32 (d, 1H), 7.41 (brs, D₂Oexchangeable, 2H), 7.46-7.50 (t, 1H), 7.72 (s, 1H), 7.73 (d, 1H); MSm/z: 482.1 (M⁺+1).

The Following Compounds were Prepared According to the Above-MentionedProcedure.

51

¹H-NMR (DMSO-d₆) δ: 2.52-2.54 (m, 4H), 3.18 (m, 4H), 7.04 (d, 1H),7.26-7.33 (m, 2H), 7.41-7.48 (m, 4H), 7.73 (d, 1H), 7.75 (d, 1H), 7.81(s, 1H); MS m/z: 464.1 (M⁺). 52

¹H-NMR (CDCl₃) δ: 2.56 (m, 4H), 3.18 (m, 4H), 7.02-7.09 (m, 1H),7.31-7.33 (m, 2H), 7.40-7.48 (m, 5H), 7.72-7.75 (d, 3H), 7.81 (s, 1H);MS m/z: 543.0 (M⁺ + 1). 53

¹H-NMR (CDCl₃) δ: 3.44 (s, 8H), 6.61-6.66 (m, 2H), 6.90 (d, 2H), 7.09(d, 2H), 7.31- 7.35 (m, 2H), 7.47-7.51 (m, 2H), 7.76 (s, 1H), 7.85-7.90(m, 1H), 8.17 (d, 2H); MS m/z: 559.1 (M⁺ + 1). 54

¹H-NMR (CDCl₃) δ: 3.38-3.41 (m, 4H), 3.71-3.74 (m, 4H), 6.61-6.66 (m,1H), 6.90 (d, 2H), 7.09 (d, 2H), 7.31-7.35 (m, 1H), 7.47- 7.51 (m, 1H),7.76 (s, 1H), 7.85-7.90 (m, 1H), 8.29 (d, 2H); MS m/z: 560.1 (M⁺ + 1).55

¹H-NMR (CDCl₃) δ: 2.94-2.97 (m, 2H), 3.60- 3.63 (m, 2H), 4.25 (s, 2H),7.06-7.08 (m, 2H), 7.18-7.21 (m, 2H), 7.41-7.47 (m, 3H), 7.61 (s, 1H),7.82 (d, 1H); MS m/z: 467.0 (M⁺ + 1). 56

¹H-NMR (DMSO-d₆) δ: 1.20-1.25 (m, 4H), 1.42-1.49 (m, 4H), 3.61 (m, 1H),4.09 (m, 1H), 4.77 (br, 1H, D₂O exchangeable), 5.14 (br, 1H, D₂Oexchangeable), 7.51-7.56 (m, 2H), 7.75-7.77 (d, 2H), 7.88-7.95 (m, 4H);MS m/z: 572.0 (M⁺ + 1). 57

¹H-NMR (CDCl₃) δ: 3.36-3.42 (m, 4H), 3.72- 3.81 (m, 4H), 6.53 (d, 1H),7.08 (d, 2H), 7.19-7.25 (m, 2H), 7.34 (d, 1H), 7.40 (d, 1H), 7.46 (d,2H), 7.68 (s, 1H), 7.82-7.85 (t, 1H), 8.28-8.31 (m, 2H); MS m/z: 541.8(M⁺). 58

¹H-NMR (CDCl₃) δ: 3.45 (m, 8H), 6.62-6.64 (m, 1H), 6.75 (d, 1H), 7.01(d, 2H), 7.20- 7.26 (m, 3H), 7.31-7.33 (m, 1H), 7.40 (br s, 2H),7.48-7.53 (m, 2H), 7.74 (d, 1H), 7.78 (s, 1H), 8.05 (d, 1H); MS m/z:540.9 (M⁺). 59

¹H-NMR (DMSO-d₆) δ: 1.03 (t, 3H), 1.39- 1.47 (m, 2H), 1.66-1.69 (m, 2H),2.11 (m, 1H), 2.84-2.90 (m, 2H), 3.66-3.69 (m, 2H), 4.00-4.06 (q, 2H),7.03-7.07 (m, 2H), 7.14- 7.15 (m, 2H), 7.36 (br, 2H, D₂O exchangeable),7.37-7.39 (d, 1H), 7.49-7.53 (t, 1H), 7.69 (s, 1H), 7.73-7.75 (d, 1H);MS m/z: 553.1 (M⁺ + 1) 60

¹H-NMR (DMSO-d₆) δ: 1.21-1.39 (m, 4H), 1.79 (m, 4H), 3.3-3.35 (m, 1H),3.94 (m, 1H), 4.53-4.54 (br, 1H, D₂O exchangeable), 6.27 (br, 1H, D₂Oexchangeable), 7.01-7.06 (m, 2H), 7.19-7.23 (m, 2H) 7.33 (br, 2H, D₂Oex), 7.40 (d, 1H), 7.53-7.61 (m, 2H), 7.79 (d, 1H); MS m/z: 511.0 (M⁺ +1). 61

¹H-NMR (DMSO-d₆) δ: 1.13-1.16 (t, 3H), 1.41-1.44 (m, 2H), 1.66-1.68 (m,2H), 2.25 (m, 1H), 2.84-2.89 (m, 2H), 3.65-3.67 (m, 2H), 4.02-4.05 (q,2H), 7.08 (d, 2H), 7.20- 7.24 (m, 3H), 7.33-7.36 (m, 2H), 7.40-7.70 (m,2H), 7.72-7.74 (m, 2H); MS m/z: 535.1 (M⁺ + 1). 62

¹H-NMR (DMSO-d₆) δ: 3.21 (m, 4H), 3.29 (m, 4H), 3.48 (m, 4H), 3.56 (m,4H), 7.10- 7.12 (m, 2H), 7.23-7.25 (m, 3H), 7.48 (s, 1H), 7.63-7.69 (m,2H), 7.76 (d. 1H); MS m/z: 535.1 (M⁺1). 63

¹H-NMR (DMSO-d₆) δ: 3.32 (m, 4H), 3.47 (m, 4H), 7.05-7.15 (m, 4H), 7.33(d, 1H), 7.42 (brs, 1H, D₂O exchangeable), 7.47-7.51 (t, 1H), 7.73 (d,1H), 7.76 (s, 1H); MS m/z: 483 (M⁺ + 1). 64

¹H-NMR (DMSO-d₆) δ: 0.82-0.87 (m, 3H), 1.15-1.27 (m, 3H), 1.70-1.79 (m,1H), 4.93 (brs, 1H, D₂O exchangeable), 7.01-7.07 (m, 2H), 7.14-7.18 (m,2H), 7.39-7.47 (m, 4H), 7.71-7.73 (m, 2H); MS m/z: 483 (M⁺ + 1). 65

¹H-NMR (DMSO-d₆) δ: 1.17-1.27 (t, 3H), 1.86-1.89 (m, 1H), 2.08-2.14 (m,2H), 2.66- 2.68 (m, 1H), 4.13 (q, 2H), 4.68-4.70 (m, 1H), 5.09 (br, 1H,D₂O exchangeable), 7.03- 7.09 (m, 2H), 7.18-7.21 (m, 2H), 7.25-7.28 (br,2H, D₂O exchangeable), 7.37-7.45 (m, 2H), 7.75-7.77 (m, 2H); MS m/z:555.1 (M⁺ + 1). 66

¹H-NMR (CDCl₃) δ: 3.38 (s, 4H), 3.51 (s, 4H), 3.88 (s, 3H), 3.89 (s,3H), 6.89-6.93 (m, 2H), 7.07-7.10 (m, 2H), 7.36 (d, 2H), 7.51-7.53 (m,1H), 7.72 (s, 1H), 7.87 (d, 1H); MS m/z: 619.8 (M⁺ + 1). 67

¹H-NMR (CDCl₃) δ: 2.99 (s, 3H), 3.47 (s, 8H), 6.60 (d, 1H), 6.66 (t,1H), 7.02-7.12 (m, 4H), 7.33 (d, 2H), 7.47 (t, 1H), 7.79 (d, 2H), 8.15(d, 1H); MS m/z: 558.1 (M⁺ + 1). 68

¹H-NMR (CDCl₃) δ: 2.99 (s, 3H), 3.44 (t, 4H), 3.73 (t, 4H), 6.53 (t,1H), 7.02-7.12 (m, 4H), 7.33 (d, 2H), 7.79 (d, 2H), 8.29 (d, 2H); MSm/z: 559.1 (M⁺ + 1). 69

¹H-NMR (CDCl₃) δ: 3.00 (s, 3H), 3.27-3.32 (m, 4H), 3.40-3.46 (m, 4H),7.05-7.10 (m, 4H), 7.33 (d, 2H), 7.80 (m, 2H), 8.03 (s, 1H); MS m/z:509.1 (M⁺ + 1). 70

¹H-NMR (CDCl₃) δ: 1.34-1.42 (m, 4H), 1.74 (d, 2H), 2.39 (t, 1H), 2.43(s, 4H), 2.69 (t, 4H), 2.98 (s, 3H), 3.95 (d, 4H), 6.99-7.05 (m, 4H),7.30 (d, 2H), 7.77 (d, 2H); MS m/z: 563.2 (M⁺ + 1). 71

¹H-NMR (CDCl₃) δ: 1.88-1.91 (m, 8H), 2.02- 2.07 (m, 4H), 2.68-2.71 (m,5H), 3.62- 3.65 (m, 2H), 6.90 (t, 2H), 7.03 (d, 1H), 7.09- 7.13 (m, 2H),7.36-7.40 (t, 1H), 7.88 (d, 1H), 8.06 (d, 1H); MS m/z: 564.2 (M⁺ + 1).72

¹H-NMR (CDCl₃) δ: 3.38 (s, 4H), 3.74 (s, 4H), 6.48 (s, 1H), 6.91 (t,2H), 7.04 (d, 1H), 7.08- 7.11 (m, 2H), 7.33 (d, 2H), 7.47-7.50 (m, 2H),7.77 (s, 1H), 7.92 (d, 1H); MS m/z: 576.1 (M⁺ + 1). 73

¹H-NMR (CDCl₃) δ: 3.14 (d, 4H), 3.47 (s, 4H), 6.91 (t, 2H), 7.02 (d,2H), 7.08-7.11 (m, 2H), 7.29-7.39 (m, 4H), 7.52 (t, 1H), 7.72 (s, 1H),7.88 (d, 1H); MS m/z: 626.1 (M⁺ + 1). 74

HPLC (purity): 96.4%; ¹H-NMR (CDCl₃) δ: 3.00 (s, 3H), 3.14 (d, 4H), 3.51(d, 4H), 6.99- 7.11 (m, 7H), 7.33 (d, 3H), 7.80 (d, 2H); MS m/z: 625.1(M⁺ + 1). 75

HPLC (purity): 89%; ¹H-NMR (CDCl₃) δ: 2.93-2.96 (m, 2H), 3.57-3.62 (m,2H), 4.22 (m, 2H), 6.87-6.91 (m, 2H), 7.07-7.12 (m, 2H), 7.31-7.37 (m,2H), 7.86 (d, 2H); MS m/z: 485.0 (M⁺ + 1). 76

¹H-NMR (CDCl₃) δ: 1.94-2.08 (m, 6H), 3.84 (d, 1H), 6.85 (t, 3H),7.06-7.10 (m, 3H), 7.52 (bs, 2H), 7.84 (d, 2H); MS m/z:. 510.1 (M⁺ + 1).77

¹H-NMR (CDCl₃) δ: 3.40 (s, 8H), 6.90-6.94 (m, 2H), 7.00-7.12 (m, 2H),7.31 (d, 1H), 7.52 (t, 1H), 7.77 (s, 1H), 7.90 (d, 1H); MS m/z: 614.0(M⁺ + 1). 78

¹H-NMR (CDCl₃) δ: 2.83 (s, 3H), 2.99 (s, 4H), 3.32 (s, 4H), 7.06-7.17(m, 4H), 7.31 (d, 1H), 7.51 (t, 1H), 7.78 (d, 1H), 7.80 (s, 1H); MS m/z:560.1 (M⁺ + 1). 79

¹H-NMR (CDCl₃) δ: 2.37 (d, 4H), 3.30 (d, 4H), 3.67 (s, 2H), 7.04-7.08(m, 2H), 7.12- 7.15 (m, 2H), 7.33 (d, 3H), 7.51 (t, 1H), 7.68 (s, 1H),7.74 (d, 1H); MS m/z: 521.1 (M⁺ + 1). 80

¹H-NMR (CDCl₃) δ: 6.97-7.03 (m, 3H), 7.15 (s, 1H), 7.31 (d, 4H), 7.46(s, 1H), 7.58 (t, 1H), 7.68 (s, 1H), 8.01 (d, 1H); MS m/z: 464.0 (M⁺ +1). 81

¹H-NMR (CDCl₃) δ: 3.04 (s, 3H), 7.03 (d, 2H), 7.09-7.15 (m, 4H), 7.50(d, 2H), 7.73 (s, 1H), 7.88 (d, 2H); MS m/z: 463.0 (M⁺ + 1). 82

R_(f) 0. (Ethylacetate:Hexanes (1:1); HPLC (purity): 95%; 1H-NMR (CDCl₃)δ: 1.02- 1.05 (m, 3H), 2.18-2.23 (m, 2H), 3.45 (s, 8H), 6.60-6.65 (m,2H), 6.85-6.89 (m, 2H), 7.07- 7.10 (m, 2H), 7.37 (d, 1H), 7.50 (d, 2H),7.94 (s, 1H), 8.02 (d, 1H), 8.13 (d. 1H); MS m/z: 615.1 (M⁺ + 1). 83

R_(f) 0.66 (Ethylacetate:Hexanes (1:1); HPLC (purity): 88.2%; ¹H-NMR(CDCl₃) δ: 0.31- 0.40 (m, 4H), 1.67-1.68 (d, 1H), 3.22-3.23 (d, 4H),3.46-3.49 (m, 4H), 7.04-7.08 (m, 2H), 7.13-7.15 (m, 2H), 7.58-7.64 (m,3H), 7.72- 7.74 (d, 1H), 7.92 (d, 1H); MS m/z: 523.1 (M⁺ + 1). 84

R_(f) 0.41 (Dichloromethane:MeOH (9:1); HPLC (purity): 97.4%; ¹H-NMR(DMSO-d₆) δ: 2.10 (s, 3H), 2.18 (s, 4H), 3.23 (s, 4H), 7.04-7.07 (m,2H), 7.11-7.15 (m, 2H), 7.34 (d, 1H), 7.41 (d, 2H), 7.47-7.51 (m, 1H),7.70- 7.76 (m, 2H); MS m/z: 496.1 (M⁺ + 1). 85

R_(f) 0.40 (Chloroform:MeOH (9.5:0.5); ¹H- NMR (DMSO-d₆) δ: 2.31 (d,3H), 7.21-7.26 (t, 2H), 7.42-7.46 (t, 5H), 7.54-7.58 (t, 1H), 7.69 (s,1H), 7.80 (d, 1H), 8.20 (d, 1H); HPLC (purity): 91.2%; MS m/z: 523.0(M⁺ + 1). 86

R_(f) 0.25 (Ethylacetate:Hexanes (7:3); HPLC (purity): 90.5%; ¹H-NMR(DMSO-d₆) δ: 2.30-2.33 (m, 4H), 3.51-3.54 (m, 4H), 7.06- 7.17 (m, 4H),7.38-7.42 (m, 3H), 7.48-7.52 (m, 1H), 7.73-7.79 (m, 2H); MS m/z: 495.0(M⁺ + 1). 87

R_(f) 0.57 (Ethylacetate:Hexanes (1:1); HPLC (purity): 85.9%; ¹H-NMR(CDCl₃) δ: 0.48- 0.49 (d, 4H), 2.88-2.92 (m, 1H), 6.87-6.91 (m, 2H),7.21-7.25 (m, 2H), 7.39-7.41 (d, 1H), 7.58-7.62 (m, 1H), 7.68 (s, 1H),7.93-7.95 (d, 1H); MS m/z: 453.0 (M⁺ + 1). 88

R_(f) 0.35 (Ethylacetate:Hexane (1:1); HPLC (purity): 97.1%; ¹H-NMR(DMSO-d₆) δ: 7.19 (d, 2H), 7.26 (s, 1H), 7.34-7.40 (m, 2H), 7.48 (s,1H), 7.53 (s, 2H), 7.60 (s, 1H), 7.63 (d, 2H), 7.69 (s, 1H), 7.71 (s,1H), 7.84 (s, 1H), 7.88 (s, 1H); MS m/z: 540.0 (M⁺ + 1). 89

R_(f) 0.56 (Chloroform:MeOH (9:1); HPLC (purity): 99.4%; ¹H-NMR(DMSO-d₆) δ: 0.88 (d, 6H), 3.03-3.06 (m, 1H), 3.08-3.18 (m, 1H),3.44-3.47 (m, 2H), 3.54-3.57 (m, 2H), 7.05-7.07 (m, 2H), 7.14-7.18 (m,2H), 7.34 (d, 1H), 7.44 (s, 2H), 7.49-7.53 (m, 1H), 7.75 (d, 2H); MSm/z: 511.1 (M⁺ + 1) 90

R_(f) 0.6 (Chloroform:MeOH (8.5:1.5); HPLC (purity): 99.2%; ¹H-NMR(CDCl₃) δ: 0.74 (d, 6H), 2.21-2.27 (m, 2H), 2.50-2.57 (m, 2H), 3.58-3.61(d, 2H), 7.03-7.08 (m, 2H), 7.13- 7.17 (m, 2H), 7.34 (d, 1H), 7.41 (s,2H), 7.47- 7.51 (m, 1H), 7.70-7.75 (m, 2H); MS m/z: 510.1 (M⁺ + 1). 91

R_(f) 0.4 (Chloroform:MeOH (8.5:1.5); HPLC (purity): 96.1%; ¹H-NMR(DMSO-d₆) δ: 0.80-0.81 (d, 3H), 2.41-2.47 (t, 1H), 2.61-2.64 (t, 2H),2.75-2.80 (t, 2H), 3.56-3.59 (t, 1H), 3.73-3.77 (d, 1H), 7.10-7.14 (t,2H), 7.19-7.22 (m, 2H), 7.40 (d, 1H), 7.47 (s, 2H), 7.54-7.57 (t, 1H),7.79 (d, 2H); MS m/z: 496.1 (M⁺ + 1). 92

R_(f) 0.42 (Ethylacetate:Hexanes (1:1); ¹H- NMR (DMSO-d₆) δ: 7.14-7.19(t, 2H), 7.31 (s, 1H), 7.35-7.43 (m, 4H), 7.48-7.51 (t, 1H), 7.68 (s,1H), 7.77 (d, 1H), 8.09 (s, 1H), 9.08 (s, 1H); HPLC (purity): 78.7%; MSm/z: 465.0 (M⁺ + 1). 93

R_(f) 0.5 (Dichloromethane:MeOH (9:1); HPLC (purity): 82.4%; ¹H-NMR(DMSO-d₆) δ: 7.03-7.12 (m, 2H), 7.31 (d, 3H), 7.46 (s, 2H), 7.52 (d,1H), 7.63 (d, 2H), 7.69 (d, 1H), 7.80-7.84 (d, 1H); MS m/z: 479.0 (M⁺ +1). 94

R_(f) 0.42 (Ethylacetate:Hexanes (3:7); HPLC (purity): 99.1%; ¹H-NMR(CDCl₃) δ: 2.51- 2.53 (m, 4H), 3.58-3.60 (m, 4H), 6.88-6.93 (t, 2H),7.05-7.08 (m, 2H), 7.33 (d, 1H), 7.49- 7.53 (m, 1H), 7.67 (s, 1H), 7.86(d, 1H); MS m/z: 499.0 (M⁺ + 1). 95

R_(f) 0.41 (Ethylacetate:Hexanes (7:3); HPLC (purity): 97%; ¹H -NMR(DMSO-d₆) δ: 2.89 (s, 3H), 3.12-3.17 (m, 2H), 3.40-3.46 (t, 2H), 6.93(d, 1H), 7.03-7.12 (m, 3H), 7.21-7.23 (m, 2H), 7.35 (s, 2H), 7.44 (d,1H), 7.60-7.64 (m, 2H), 7.80 (d, 1H); MS m/z: 534.0 (M⁺ + 1). 96

R_(f) 0.55 (Chloroform:MeOH (9:1); HPLC (purity): 98.8%; ¹H-NMR(DMSO-d₆) δ: 1.06-1.07 (d, 3H), 2.84 (d, 1H), 2.90 (s, 3H), 3.01 (s,1H), 3.11-3.14 (d, 2H), 3.19-3.26 (t, 1H), 3.39-3.42 (d, 1H), 3.78-3.81(d, 1H), 7.05-7.09 (t, 2H), 7.15-7.18 (t, 2H), 7.36 (s, 1H), 7.51-7.55(t, 2H), 7.74-7.79 (t, 1H); MS m/z: 574.0 (M⁺ + 1). 97

R_(f) 0.3 (chloroform:MeOH (9:1); HPLC (purity): 84.8%; ¹H-NMR (CDCl₃)δ: 1.86- 1.89 (m, 1H), 2.34-2.37 (m, 1H), 2.59 (s, 4H), 3.21-3.23 (m,1H), 3.28-3.30 (m, 1H), 4.04- 4.11 (m, 2H), 6.93-6.99 (m, 5H), 7.04 (d,1H), 7.10 (d, 2H), 7.36-7.39 (t, 3H), 7.90 (d, 1H), 8.14 (s, 1H); MSm/z: 622.1 (M⁺ + 1). 98

R_(f) 0.61 (Ethylacetate:Hexanes (8:2); HPLC (purity): 99%; ¹H-NMR(DMSO-d₆) δ: 3.21 (d, 4H), 3.43-3.48 (m, 4H), 7.09 (d, 2H), 7.21-7.30(m, 4H), 7.43-7.47 (m, 3H), 7.72 (d, 1H), 7.79 (s, 1H); MS m/z: 464.8(M⁺ + 1).

Example 99 Synthesis of3-[6-(4-fluorophenyl)-4-(2-morpholin-4-ylethoxy)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide

To a solution of6-(4-fluorophenyl)-5-phenyl-2-(trifluoromethyl)pyrimidin-4(3H)-one (1 g,3.0 mmol) in acetonitrile (5 ml) was added chloroethyl morpholine (0.84g, 4.5 mmol) and caesium carbonate (3 g, 9 mmol). The reaction mixturewas refluxed at 70-80° C. for 5 hours. Subsequently the reaction slurrywas poured into the water and extracted with dichloromethane (3×30 ml).The organic layer was dried over anhydrous sodium sulphate andevaporated at reduced pressure to give the desired compound that wassubjected to further transformation without purification.

To pyrimidine (0.5 g, 1.2 mmol) was added chlorosulphonic acid (10 ml,0.150 mol) in ice-cold condition. The reaction mixture was stirred atroom temperature for 28 hours. The reaction mixture was poured intowater and extracted with dichloromethane (3×25 ml). The organic layerwas dried over anhydrous sodium sulphate and evaporated at reducedpressure to give the desired compound that was subjected to furthertransformation without purification.

To the stirring solution of chlorosulphonyl derivative (0.5 g, 0.917mmol) in dichloromethane (5 ml) was purged ammonia gas for 30 minutesthrough ammonia purging setup. The reaction slurry was poured into thewater and extracted with dichloromethane (3×25 ml). The organic layerwas dried over anhydrous sodium sulphate and upon evaporation at reducedpressure it gave the desired solid (0.379 g, 78.6%), R_(f) 0.51(Ethylacetate: Hexanes, 7:3); HPLC (purity): 94.6%; ¹H-NMR (DMSO-d₆) δ:2.33 (s, 4H), 2.61-2.63 (t, 2H), 3.43-3.49 (m, 4H), 4.54-4.57 (t, 2H),7.13-7.17 (m, 3H), 7.37-7.40 (m, 3H), 7.44-7.47 (m, 2H), 7.55 (d, 1H),7.80 (d, 1H); MS m/z: 527.1 (M⁺+1).

Example 100 Synthesis of3-{4-[4-(2-cyanoethyl)piperazin-1-yl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide

To a solution of amine (0.1 g, 0.206 mmol) in dichloromethane (1.5 ml)was added acrylonitrile (0.016 ml, 0.248 mmol) and triethyl amine (0.033ml, 0.25 mmol). The reaction slurry was stirred at room temperature for18 hours and then it was poured into the ice-cold water and extractedwith dichloromethane (2×20 ml). The organic layer was dried overanhydrous sodium sulphate and evaporated to give the solid that wassubjected to column chromatography using a gradient of methanol indichloromethane (0-1%). Yield-0.05 g (45%), R_(f) 0.52 (Dichloromethane:MeOH (9:1); HPLC (purity): 96.1%; ¹H-NMR (DMSO-d₆) δ: 2.35 (s, 6H), 3.26(s, 6H), 7.06-7.14 (m, 5H), 7.42 (s, 1H), 7.73 (d, 2H); MS m/z: 535.1(M⁺+1).

The Following Compounds were Prepared by the Above Procedures

101

R_(f) 0.59 (Chloroform:MeOH (9:1); HPLC (purity): 98.7%; ¹H-NMR(DMSO-d₆) δ: 0.80-0.86 (m, 3H), 2.13 (t, 1H), 2.39 (t, 1H), 2.81 (t,1H), 2.96 (t, 1H), 3.40-3.54 (m, 2H), 3.87-3.90 (d, 1H), 7.03-7.08 (t,2H), 7.13-7.16 (m, 2H), 7.35 (d, 1H), 7.39 (d, 4H), 7.47-7.51 (t, 1H),7.69-7.74 (t, 3H), 8.45 (d, 1H); MS m/z: 587.1 (M⁺ + 1). 102

R_(f) 0.49 (Ethylacetate:Hexanes (1:1); HPLC (purity): 99.9%; ¹H-NMR(DMSO-d₆) δ: 0.87 (d, 3H), 1.99-2.01 (m, 1H), 2.34 (s, 1H), 2.44- 2.46(m, 1H), 2.82-2.87 (t, 2H), 3.11 (d, 1H), 3.46 (d, 2H), 3.71 (s, 3H),3.83-3.86 (m, 1H), (6.79-6.85 (t, 3H), 7.03-7.07 (t, 2H), 7.13- 7.19 (m,3H), 7.22 (s, 1H), 7.34 (d, 2H), 7.47- 7.51 (t, 1H), 7.53-7.54 (t, 2H);MS m/z: 616.1 (M⁺ + 1). 103

R_(f) 0.58 (Chloroform:MeOH (9:1); HPLC (purity): 95.1%; ¹H-NMR(DMSO-d₆) δ: 2.34 (s, 4H), 3.28 (s, 4H), 3.59 (s, 2H), 7.04-7.08 (t,2H), 7.11-7.15 (m, 2H), 7.35 (s, 1H), 7.38- 7.39 (d, 4H), 7.49 (s, 1H),7.70-7.73 (t, 3H), 8.46-8.47 (d, 1H); MS m/z: 573.1 (M⁺ + 1). 104

R_(f) 0.42 (Ethylacetate:Hexanes (1:1); HPLC (purity): 94.5%; ¹H-NMR(DMSO-d₆) δ: 2.49 (s, 4H), 3.25 (s, 4H), 3.39 (s, 2H), 3.71 (s, 3H),6.78-6.83 (t, 3H), 7.03-7.08 (t, 2H), 7.11-7.15 (m, 1H), 7.2 (s, 1H),7.34 (d, 1H), 7.38 (s, 2H), 7.48 (s, 1H), 7.69-7.72 (t, 1H);. MS m/z:602.1 (M⁺ + 1). 105

R_(f) 0.43 (Dichloromethane:MeOH (9:1); HPLC (purity): 95.7%; ¹H-NMR(CDCl₃) δ: 2.42-2.44 (m, 4H), 2.52-2.55 (m, 2H), 3.32- 3.34 (t, 4H),3.59-3.65 (m, 2H), 6.88-6.93 (t, 2H), 7.06-7.10 (m, 2H), 7.31 (d, 1H),7.47 (d, 1H), 7.72 (s, 1H), 7.84 (d, 1H); MS m/z: 526.1 (M⁺ + 1). 106

R_(f) 0.29 (Dichloromethane:MeOH (9:1); HPLC (purity): 96.6%; ¹H-NMR(CDCl₃) δ: 3.42- 3.48 (d, 4H), 3.85 (s, 4H), 6.91-6.95 (m, 2H),7.08-7.17 (m, 4H), 7.29-7.31 (d, 2H), 7.49-7.53 (m, 1H), 7.83-7.85 (d,1H), 7.89-7.91 (d, 1H); MS m/z: 592.0 (M⁺ + 1).

Example 107 Synthesis of3-[4-(1,1-dioxido-1,3-thiazolidin-3-yl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide

To a mixture of3-[4-(4-fluorophenyl)-6-(1,3-thiazolidin-3-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide; (0.2 g, 0.41 mmol) in methanol(3 ml) was added oxone (0.51 g, 0.83 mmol) in water (6 ml). Theresulting slurry was stirred for 27 hours at room temperature. Thereaction mixture was poured into water and extracted with ethylacetate(3×30 ml). The organic layer was dried over anhydrous sodium sulphateand evaporated at reduced pressure to give a solid, which was subjectedto column chromatography using a gradient of ethylacetate in hexane(0-25%). Yield-0.14 g (65.7%); R_(f) 0.65 (Ethylacetate:Hexanes (7:3);HPLC (purity): 98.7%; ¹H-NMR (DMSO-d₆) δ: 3.39-3.46 (m, 2H), 3.84-3.86(t, 2H), 4.05 (s, 2H), 7.06-7.10 (t, 2H), 7.16-7.19 (t, 2H), 7.41 (s,2H), 7.46 (s, 1H), 7.52-7.56 (t, 1H), 7.74 (s, 1H), 7.79 (d, 1H); MSm/z: 517.0 (M⁺+1).

108

R_(f) 0.15 (Ethylacetate: Hexanes (7:3); HPLC (purity): 97%; ¹H-NMR(DMSO-d₆) δ: 2.89 (d, 1H), 3.17 (d, 1H), 3.85 (d, 1H), 3.96-3.99 (d,2H), 4.23 (s, 1H), 7.05-7.10 (t, 2H), 7.17-7.21 (m, 2H), 7.37 (s, 2H),7.41-7.51 (t, 2H), 7.77 (d, 2H); MS m/z: 501.0 (M⁺ + 1).

Preparation of the Following Compounds was Carried Out Using theWell-Known procedure of treating an amine with the corresponding acidchloride in presence of a base (triethylamine) in dichloromethane(solvent) and usual workup and purification to provide the desiredcompounds. Example 113 was obtained by treating the ketone witho-methylhydroxylamine and a base followed by usual workup andpurification.

109

R_(f) 0.40 (Dichloromethane:MeOH (9:1); HPLC (purity): 93.3%; ¹H-NMR(DMSO- d₆) δ: 3.43-3.52 (m, 8H), 7.07-7.17 (m, 4H), 7.36 (d, 1H),7.42-7.45 (d, 2H), 7.50-7.54 (t, 1H), 7.76 (d, 2H); MS m/z: 578.0 (M⁺ +1). 110

R_(f) 0.59 (Chloroform:MeOH (3:7); HPLC (purity): 82%; ¹H-NMR (DMSO-d₆)δ: 3.21-3.22 (d, 4H), 3.34 (s, 2H), 3.55 (s, 2H), 7.06-7.16 (m, 4H),7.26-7.29 (m, 2H), 7.36- 7.41 (m, 4H), 7.49 (d, 2H), 7.74 (d, 2H); MSm/z: 604.1 (M⁺ + 1). 111

R_(f) 0.75 (Dichloromethane:MeOH (9:1); HPLC (purity): 96.2%; ¹H-NMR(CDCl₃) δ: 3.26 (s, 4H), 3.50 (s, 4H), 6.91-6.96 (m, 2H), 7.10-7.14 (m,2H), 7.33 (d, 1H), 7.52- 7.56 (t, 1H), 7.80 (s, 1H), 7.91-7.96 (m, 1H);MS m/z: 580.0 (M⁺ + l). 112

R_(f) 0.42 (Dichloromethane:MeOH (9:1); HPLC (purity): 95.4%; ¹H-NMR(DMSO- d₆) δ: 0.66-0.69 (d, 4H), 1.86-1.89 (t, 1H), 3.22 (s, 4H), 3.51(s, 4H), 7.06-7.16 (m, 4H), 7.36 (d, 1H), 7.44 (s, 2H), 7.49-7.52 (t,1H), 7.74-7.77 (d, 2H); MS m/z: 550.1 (M⁺ + 1). 113

R_(f) 0.61 (Ethylacetate:Hexanes (7:3); HPLC (purity): .95.2%; ¹H-NMR(DMSO-d₆) δ: 2.20-2.23 (t, 4H), 2.38-2.41 (t, 4H), 3.70 (s, 3H),7.05-7.16 (m, 4H), 7.37 (d, 3H), 7.47- 7.51 (t, 1H), 7.74 (d, 2H); MSm/z: 524.1 (M⁺ + 1).

Example 114 Synthesis of3-{6-(4-fluorophenyl)-4-[(3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)amino]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide

To a solution of hydrazine (0.15 g, 0.351 mmol) in chloroform (5 ml) wasadded citraconic anhydride (0.097 ml, 3 mmol). The resulting solutionwas stirred at 60° C. for 18 hours. Subsequently water (20 ml) anddichloromethane (3×25 ml) were added to the reaction mixture. Theorganic layer was separated, dried over anhydrous sodium sulphate andconcentrated in vacuo. The resulting residue was subjected to columnchromatography using a gradient of methanol in dichloromethane (0-1.5%).Yield—0.07 g (38.2%), R_(f) 0.44 (Dichloromethane: Methanol (9:1); HPLC(purity): 89.2%; ¹H-NMR (CDCl₃) δ: 2.10 (s, 3H), 6.46 (s, 1H), 6.92-6.96(m, 2H), 7.29-7.33 (m, 2H), 7.47 (d, 1H), 7.57-7.61 (m, 1H), 7.95 (d,1H), 8.02 (s, 1H); MS m/z: 522.0 (M⁺+1).

The Following Compound was Prepared According to the Above-MentionedProcedure

115

R_(f) 0.39 (Dichloromethane:MeOH (9:1); HPLC (purity): 91.93%; ¹H-NMR(DMSO- d₆) δ: 7.07-7.12 (m, 2H), 7.29-7.33 (d, 4H), 7.4 (s, 1H),7.53-7.57 (m, 2H), 7.63-7.67 (m, 1H), 7.75 (s, 1H), 7.86 (d, 1H), 9.57(s, 1H); MS m/z: 508.0 (M⁺ + 1)

Example 116 Synthesis of3-[6-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-4-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide

Step 1 Preparation of 1-[5-(trifluoromethyl)pyridin-2-yl]piperazine

Piperazine (1.2 g, 13.77 mM) was heated with2-chloro-5-(trifluoromethyl)pyridine (0.5 g, 2.75 mmol) in THF (2 mL)for 2 hours. Subsequently the reaction mixture was poured onto crushedice and extracted with ethyl acetate. The organic layer was washed withsodium bicarbonate and evaporated to furnish the required product.

Step 2 Preparation of3-[6-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide

A solution of3-[6-chloro-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide(0.1 g, 0.242 mmol) in pyridine (2 ml) was treated with1-[5-(trifluoromethyl)pyridin-2-yl]piperazine (0.3 g, 0.68 mmol) and thereaction mixture was stirred for 1 hour at room temperature.Subsequently the reaction mixture was poured onto crushed ice containingtwo drops of concentrated hydrochloric acid, extracted with ethylacetate (25 ml) and the organic layer was washed with brine andevaporated. The title compound was obtained by column chromatographicpurification of the crude material with 30% ethyl acetate in hexane.¹H-NMR (DMSO-d₆) δ: 3.33-3.37 (m, 4H), 3.56 (m, 4H), 6.86-6.88 (d, 1H),7.10-7.12 (d, 2H), 7.22-7.29 (m, 3H), 7.35-7.37 (m, 1H), 7.44-7.48 (m,1H), 7.74-7.79 (m, 3H), 8.38 (s, 1H); MS m/z: 608.8 (M⁺).

Example 117 Synthesis of3-[6-{4-[2,6-dimethoxypyrimidin-4-yl]piperazin-1-yl}-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide

Step 1 Preparation of 2,4-dimethoxy-6-piperazin-1-ylpyrimidine

Piperazine (1.23 g, 14.32 mmol) was treated with 6-chloro-2,4-dimethoxypyrimidine (0.5 g, 2.86 mmol) in acetonitrile (5 mL) and the reactionmixture was stirred at room temperature for 6 hours. Subsequently thereaction mixture was poured onto ice-cold water (25 ml) and extractedwith ethyl acetate (25 ml). The organic layer was washed with aqueoussodium bicarbonate solution and evaporated to furnish the requiredcompound.

Step 2 Preparation of3-[6-{4-[2,6-dimethoxypyrimidin-4-yl]piperazin-1-yl}-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide

A solution of3-[6-chloro-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide(0.1 g, 0.242 mmol) in pyridine (1.5 ml) was treated with2,4-dimethoxy-6-piperazin-1-ylpyrimidine (0.081 g, 0.363 mmol) and thereaction mixture was stirred for 8 hours. Subsequently the reactionmixture was poured onto ice-cold water and extracted with ethyl acetate(25 ml). The organic layer was washed with brine and evaporated tofurnish the title compound. ¹H-NMR (CDCl₃) δ: 3.39-3.41 (m, 4H),3.51-3.52 (m, 4H), 3.87-3.88 (s, 6H), 7.07-7.09 (d, 2H), 7.20-7.26 (m,3H), 7.30-7.32 (m, 1H), 7.47-7.61 (t, 1H), 7.64 (s, 1H), 7.82-7.87 (m,2H); MS m/z: 601.8 (M⁺).

Example 118 Synthesis of3-[6-{4-[5-(nitro)pyridin-2-yl]piperazin-1-yl}-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide

Step 1 Preparation of 1-(5-nitropyridin-2-yl)piperazine

2-Bromo-5-nitropyridine (0.3 g, 1.48 mmol) was treated with piperazine(0.64 g, 7.89 mmol) in tetrahydrofuran (4 ml) and the reaction mixturewas stirred for 30 minutes. Subsequently the reaction mixture was pouredonto ice-cold water (25 ml) and extracted with ethyl acetate (25 ml).The organic layer was washed with brine and evaporated to furnish theproduct.

Step 2 Preparation of 3-[6-{4-[5-(nitro)pyridin-2-yl]piperazin-1-yl}-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide

The solution of3-[6-chloro-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide(0.1 g, 0.242 mmol) in pyridine (2 ml) was treated with1-(5-nitropyridin-2-yl)piperazine (0.075 g, 0.363 mmol) and stirred for11 hours. Subsequently the reaction mixture was poured onto ice-coldwater and extracted with ethyl acetate (25 ml). The organic layer waswashed with brine and evaporated to give the crude material.Purification by column chromatography (elution with 70% ethyl acetate inhexane) yielded the title compound. ¹H-NMR (CDCl₃) δ: 3.45-3.46 (m, 4H),3.72 (m, 4H), 6.52-6.54 (d, 1H), 7.08-7.11 (d, 2H), 7.21-7.26 (m, 2H),7.32-7.34 (d, 1H), 7.40-7.42 (d, 1H), 7.50 (m, 1H), 7.68 (s, 1H),7.84-7.89 (m, 1H), 8.21-8.23 (d, 1H), 8.99 (s, 1H); MS m/z: 585.8 (M⁺).

Example 119 Synthesis of3-[6-{4-[5-(amino)pyridin-2-yl]piperazin-1-yl}-4-[4-fluorophenyl]-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide

3-[6-{4-[5-(Nitro)pyridin-2-yl]piperazin-1-yl}-4-[4-fluorophenyl]-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide(0.13 g, 0.22 mmol) was taken in concentrated hydrochloric acid (1.5 ml)and to this tin (II) chloride dihydrate (0.145 g, 0.65 mmol) was addedand the reaction mixture was stirred for 24 hours at room temperature.Subsequently the reaction mixture was poured onto crushed ice,neutralized with sodium bicarbonate, and extracted with ethyl acetate.Evaporation of the solvent yielded the required product. ¹H-NMR(DMSO-d₆) δ: 3.13 (m, 4H), 3.30 (m, 4H), 4.58 (br, 2H, D₂Oexchangeable), 6.57-6.59 (m, 1H), 6.88 (d, 1H), 7.04-7.09 (m, 2H),7.12-7.14 (m, 2H), 7.39 (br, 2H, D₂O exchangeable), 7.41 (d, 1H),7.50-7.55 (m, 2H), 7.73-7.77 (m, 2H); MS m/z: 574.1 (M⁺+1).

Example 120 Synthesis of4-[5-(acetylamino)pyridin-2-yl]piperazin-1-yl-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidine

4-Chloro-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidine (0.15 g, 0.35 mmol) was treated with1-(5-nitropyridin-2-yl)piperazine (0.087 g, 0.418 mmol) anddiisopropylethylamine (0.06 mL, 0.35 mmol), acetonitrile (2.5 ml) andthe reaction mixture was heated at 60-65° C. for 2 hours. Subsequentlythe reaction mixture was precipitated by the addition, of diisopropylether (2 ml). The above-obtained solid (0.11 g, 0.182 mmol) was taken upin acetic acid (2 ml) and tin (II) chloride dihydrate (0.123 g, 0.182mmol) was added to it. Stirring was continued further for 11 hours andthen the reaction mixture was poured onto ice-cold water and extractedwith ethyl acetate (2×25 ml). After neutralization with sodiumbicarbonate, the organic layer was evaporated to obtain the crudematerial, which was purified by column chromatography (2% MeOH indichloromethane) to yield the title compound. ¹H-NMR (DMSO-d₆) δ: 1.99(s, 3H), 3.19 (s, 3H), 3.29-3.40 (m, 8H), 6.77 (d, 1H), 7.19-7.23 (m,2H), 7.31-7.34 (m, 2H), 7.36 (d, 2H), 7.74 (d, 1H), 7.80 (d, 2H), 8.24(d, 1H), 9.77 (s, 1H, D₂O exchangeable); MS m/z: 615.1 (M⁺+1).

Example 121 Synthesis ofN-({3-[4-pyridin-2-yl]piperazin-1-yl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]phenyl}sulfonyl)acetamide

3-[4-{4-(5-Pyridin-2-yl)piperazin-1-yl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide (0.1 g, 0.178 mmol) was treatedwith acetyl chloride (0.35 ml) and the reaction mixture was stirred for40 hours. Subsequently it was poured onto crushed ice, extracted withdichloromethane (25 ml) and washed with brine. The organic layer wasevaporated to furnish the required compound. ¹H-NMR (DMSO-d₆) δ: 1.81(s, 3H), 3.32-3.37 (m, 8H), 6.62 (t, 1H), 6.75 (d, 1H), 7.02-7.07 (m,2H), 7.11-7.14 (m, 2H), 7.50-7.59 (m, 3H), 7.80 (s, 1H), 7.84 (d, 1H),8.06 (d, 1H), 12.09 (brs, 1H, D₂O exchangeable); MS m/z: 601.1 (M⁺+1).

The Following Compound was Prepared According to the Procedure DescribedAbove.

122

¹H-NMR (CDCl₃) δ: 1.02-1.05 (t, 3H), 2.18-2.24 (q, 2H), 3.45-3.49 (m,8H), 6.60-6.65 (m, 2H), 6.85-6.89 (m, 2H), 7.08-7.10 (m, 2H), 7.37 (d,1H), 7.47-7.50 (m, 2H), 7.94 (s, 1H), 8.02 (d, 1H), 8.12 (d, 1H); MSm/z: 615.1 (M⁺ + 1).

Example 123 Synthesis of1-{5-[3-(aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}piperidine-4-carboxylicacid

A solution of ethyl1-{5-[3-(aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}piperidine-4-carboxylate(0.4 g, 0.725 mmol) in tetrahydrofuran (4 ml) was treated with lithiumhydroxide monohydrate (0.036 g, 0.87 mmol) in water (0.2 ml) and wasstirred for 17 hours. Subsequently the reaction mixture was poured ontoice-cold water, acidified with dilute hydrochloric acid and extractedwith dichloromethane (25 ml). Evaporation of organic layer furnished therequired product. ¹H-NMR (DMSO-d₆) δ: 1.39 (m, 2H), 1.64 (m, 2H), 2.09(m, 1H), 2.84-2.89 (m, 2H), 3.66 (m, 2H), 7.02-7.07 (m, 2H), 7.07-7.13(m, 2H), 7.37-7.39 (m, 2H), 7.49-7.53 (m, 1H), 7.69 (s, 1H), 7.72-7.74(d, 1H), 12.25 (br, 1H, D₂O exchangeable); MS m/z: 525.0 (M⁺+1).

Example 124 Synthesis of4-[4-(methoxyaminocarbonyl)piperidin-1-yl}-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidine

A solution of1-{5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-4-yl}piperidine-4-carboxylicacid (0.15 g, 0.30 mmol) in dichloromethane (5 ml) was treated witho-methyl hydroxylamine hydrochloride (0.028 g, 0.30 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.127 g,0.663 mmol), 1-hydroxybenzotriazole (0.008 g, 0.066 mmol) anddiisopropylethylamine (0.042 g, 0.33 mmol). After 2 hours of stirringthe reaction mixture was poured onto ice-cold water, extracted withdichloromethane and washed with brine. Evaporation of the organic layerfurnished the required compound. ¹H-NMR (DMSO-d₆) δ: 1.46 (m, 4H), 2.14(m, 1H), 2.73-2.78 (m, 2H), 3.18 (s, 3H), 3.53 (s, 3H), 3.81-3.84 (m,2H), 7.24 (d, 2H), 7.31-7.36 (m, 5H), 7.75 (d, 2H), 11.01 (br.s, 1H, D₂Oexchangeable); MS m/z: 535.1 (M⁺+1).

The Following Compound was Prepared According to the Above-MentionedProcedure

125

R_(f) 0.36 (Dichloromethane: MeOH (9:1); HPLC (purity): 94.1%; ¹H-NMR(DMSO- d₆) δ: 1.31-1.34 (d, 2H), 1.45 (d, 2H), 1.99 (t, 1H), 2.79-2.85(t, 2H), 3.63- 3.66 (d, 2H), 7.05- 7.09 (t, 2H), 7.13-7.16 (t, 2H), 7.33(d, 1H), 7.39 (d, 1H), 7.47-7.51 (t, 2H), 7.56 (s, 1H), 7.71-7.74 (d,1H); MS m/z: 539.0 (M⁺ + 1).

Example 126 Synthesis of methyl3-methoxy-4-({6-[4-(methylsulfonyl)phenyl]-5-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}oxy)benzoate

4-Chloro-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidine (0.5 g, 1.63 mmol), methyl vanillate (0.423 g, 2.33mmol), potassium carbonate (0.24 g, 1.74 mmol) and acetonitrile (7 ml)were stirred at room temperature for 2 hours and subsequently thereaction mixture was refluxed for 6 hours. Further, potassium carbonate(0.08 g, 0.58 mmol) and vanillic ester (0.12 g, 0.66 mmol) were added tothe reaction mixture and the refluxing was continued for another 4hours. Subsequently the reaction mixture was poured onto ice-cold water,extracted with ethyl acetate (25 mL) and washed with brine solution.Evaporation of the organic layer yielded the required product. ¹H-NMR(DMSO-d₆) δ: 3.24 (s, 3H), 3.81 (s, 3H), 3.88 (s, 3H), 7.26-7.30 (m,2H), 7.44 (d, 1H), 7.49-7.53 (m, 2H), 7.61-7.69 (m, 4H), 7.91 (d, 2H);MS m/z: 576.8 (M⁺+1).

Example 127 Synthesis of3-methoxy-4-({6-(4-fluorophenyl)-5-[3-(aminosulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-4-yl}oxy)-N-methoxybenzamide

Step 1 Preparation of 4-hydroxy-N-3-dimethoxybenzamide

Vanillic acid (1.0 g, 5.93 mmol), o-methylhydroxylamine (0.5 g, 5.99mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.37g, 7.12 mmol), 1-hydroxybenzotriazole (0.095 g, 0.713 mmol) anddiisopropylethylamine (0.76 g, 5.93 mmol) in dichloromethane 8 ml) werestirred for 2 hours. Subsequently the reaction mixture was poured ontocold water and extracted with dichloromethane (50 ml). The crudematerial obtained on evaporation of the organic layer was purified bycolumn chromatography; elution with 1.5% MeOH in dichloromethane yieldedthe pure compound.

Step 2 Preparation of3-methoxy-4-({6-(4-fluorophenyl)-5-[3-(aminosulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-4-yl}oxy)-N-methoxybenzamide

A suspension of3-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide(0.15 g, 0.35 mmol), 4-hydroxy-N,3-dimethoxybenzamide (0.102 g, 0.52mmol) and potassium carbonate (0.52 mmol) in acetonitrile (3 ml) wereheated to reflux (65° C.) for 2 hours. Subsequently the reaction mixturewas poured onto ice-cold water, extracted with dichloromethane (50 ml)and washed with brine.

Evaporation of the organic layer furnished a crude material, which waspurified by column chromatography; elution with 2% MeOH indichloromethane furnished the required compound. ¹H-NMR (DMSO-d₆) δ:3.73 (s, 3H), 3.79 (s, 3H), 7.16-7.20 (m, 2H), 7.37 (d, 1H), 7.41-7.45(m, 5H), 7.53 (s, 1H), 7.62-7.63 (d, 2H), 7.85 (d, 1H), 7.89 (s, 1H).11.9 (s, 1H); MS m/z: 593 (M⁺+1).

The Following Compound was Made by the Above-Mentioned Procedure

128

¹H-NMR (DMSO-d₆) : 3.24 (s, 3H), 3.73 (s, 3H), 3.79 (s, 3H), 7.26-7.30(m, 2H), 7.36-7.39 (m, 1H), 7.42 (s, 1H), 7.49 (d, 2H), 7.51-7.54 (m,2H), 7.61-7.63 (m, 1H), 7.90 (d, 2H), 11.85 (br, 1H, D₂O exchangeable);MS m/z: 592 (M⁺ + 1).

Example 129 Synthesis of5-amino-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-methyl-1H-pyrazole-4-carbonitrile

1-Methoxyethylidene malononitrile (0.17 g, 1.36 mmol) (prepared frommalononitrile and triethyl orthoacetate by heating with aceticanhydride) was heated with4-hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.15 g, 0.45mmol) in methanol (6 ml), overnight at 60-65° C. The solid thatseparated out from the reaction mixture was filtered and washed withmethanol (5 ml), to yield the title compound. ¹H-NMR (DMSO-d₆) δ: 1.97(s, 3H), 6.97 (br, 2H, D₂O exchangeable), 7.07 (d, 2H), 7.26-7.38 (m,7H), 7.40-7.41 (m, 1H); MS m/z: 421.1 (M⁺+1).

Example 130 Synthesis of ethyl5-amino-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-1H-pyrazole-4-carboxylate

Ethyl 2-cyano-3,3-bis(methylthio)acrylate (0.3 g, 1.36 mmol) was heatedwith 4-hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.15 g,0.45 mmol) in methanol (6 ml) overnight at 60-65° C. The solid thatseparated out from the reaction mixture was filtered and washed withisopropylalcohol (5 ml), to furnish the required compound. ¹H-NMR(DMSO-d₆) δ: 1.22-1.25 (t, 3H), 3.16 (s, 3H), 4.11-4.17 (q, 2H), 4.36(br, 2H, D₂O exchangeable), 7.12 (d, 2H), 7.25-7.35 (m, 7H), 7.69 (d,1H); MS m/z: 500.1 (M⁺+1).

The Following Compounds were Prepared According to the ProcedureDescribed Above.

Ex. Structure Analytical Data 131

¹H-NMR (CDCl₃) δ: 6.11 (s, 1H), 6.99- 7.01 (d, 2H), 7.23-7.35 (d, 8H);MS m/z: 407.1 (M⁺ + 1). 132

¹H-NMR (CDCl₃) δ: 0.86 (s, 9H), 5.21 (br, 2H, D2O exchangeable), 5.35(s, 1H), 7.00-7.03 (d, 2H), 7.19-7.29 (m, 8H); MS m/z: 438.1 (M⁺ + 1).133

¹H-NMR (CDCl₃) δ: 2.04 (s, 3H), 2.21 (s, 3H), 5.85 (s, 1H), 6.94 (d,2H), 7.18- 7.32 (m, 6H), 7.35 (d, 2H); MS m/z: 395.1 (M⁺ + 1). 134

¹H-NMR (CDCl₃) δ: 1.86 (s, 3H), 6.44 (s, 2H), 6.93-6.98 (m, 2H),7.20-7.29 (m, 4H), 7.40-7.44 (m, 1H), 7.66 (s, 1H), 7.83-7.88 (m, 1H);MS m/z: 518.0 (M⁺ + 1). 135

¹H-NMR (CDCl₃) δ: 1.33-1.35 (t, 3H), 1.56 (s, 3H), 4.27-4.32 (m, 2H),6.92- 6.96 (m, 2H), 7.18-7.20 (m, 2H), 7.37- 7.47 (m, 2H), 7.66 (s, 1H),7.81-7.84 (m, 1H); MS m/z: 599.0 (M⁺ + 1). 136

¹H-NMR (CDCl₃) δ: 3.02 (s, 3H), 6.63 (s, 1H), 7.02 (d, 2H), 7.29-7.31(m, 2H), 7.35 (m, 1H), 7.55 (d, 2H), 7.83 (d, 2H), 8.40 (s, 1H); MS m/z:513.0 (M⁺ + 1). 137

¹H-NMR (CDCl₃) δ: 6.56 (bs, 2H), 7.00 (d, 2H), 7.22-7.34 (m, 5H), 8.28(s, 2H); MS m/z: 441.0 (M⁺ + 1). 138

¹H-NMR (CDCl₃) δ: 3.00 (s, 3H), 3.54 (q, 2H), 6.42 (d, 2H), 6.84 (d,1H), 7.00- 7.05 (m, 1H), 7.20-7.24 (m, 2H), 7.31- 7.33 (m, 2H),7.45-7.51 (m, 3H), 7.77- 7.81 (m, 2H), 7.96 (d, 2H); MS m/z: 607.0 (M⁺ +1). 139

¹H-NMR (CDCl₃) δ: 0.92 (s, 9H), 3.92 (s, 3H), 6.86 (s, 1H), 7.00-7.03(m, 2H), 7.21-7.29 (m, 10H), 7.96 (d, 2H), 11.24 (s, 1H); MS m/z: 572.1(M⁺ + 1). 140

¹H-NMR (CDCl₃) δ: 0.92 (s, 9H), 6.88 (s, 1H), 7.00-7.01 (m, 2H),7.23-7.29 (m, 6H), 7.30 (d, 2H), 7.52 (d, 2H), 7.73 (d, 1H), 7.94 (d,1H), 11.40 (s, 1H); MS m/z: 560.1 (M⁺ + 1). 141

¹H-NMR (CDCl₃) δ: 0.92 (s, 9H), 6.91 (s, 1H), 7.01-7.03 (m, 2H),7.23-7.31 (m, 8H), 7.81 (d, 2H), 8.10 (d, 2H), 11.52 (s, 1H); MS m/z:610.1 (M⁺ + 1). 142

¹H-NMR (CDCl₃) δ: 1.35 (t, 3H), 1.59 (s, 3H), 3.01 (s, 3H), 4.27-4.32(dd, 2H), 7.02 (s, 2H), 7.38-7.41 (m, 5H), 7.78- 7.81 (m, 2H); MS m/z:578.0 (M⁺ + 1).

Example 143 Synthesis of5-amino-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-N-phenyl-1H-pyrazole-4-carboxamide

Step 1 Preparation of 2-cyano-3,3-bis(methylthio)-N-phenylacrylamide

2-Cyano-N-phenylacetamide (1.0 g, 6.25 mmol) was treated with sodiumhydride 60% (1.13 g, 28.13 mmol) in tetrahydrofuran under ice-coldconditions and stirring for 15 minutes. Carbon disulfide (0.9 mL, 15.65mmol) was added to the above mixture and the stirring was continued atice-cold condition for a further 15 minutes. Methyliodide (2.22 g, 15.65mmol) was added to the above under the same ice-cold conditions and thestirring was continued at room temperature overnight. Subsequently thereaction mixture was acidified with dilute hydrochloric acid (5 ml) andextracted with ethyl acetate (50 ml). Evaporation of the organic layeryielded an oily crude material.

Step 2 Preparation of5-amino-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-N-phenyl-1H-pyrazole-4-carboxamide

A solution of 4-hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine(0.2 g, 0.63 mmol) in methanol (6 ml) was heated with2-cyano-3,3-bis(methylthio)-N-phenylacrylamide (0.5 g, 1.89 mmol),overnight, at 60-65° C. The solid that separated out was filtered andwashed with isopropyl alcohol (3 ml) to yield the required product.¹H-NMR (CDCl₃) δ: 1.98 (s, 3H), 6.96-7.57 (m, 15H), 7.25-7.30 (2H, D₂Oexchangeable), 8.86 (br, 1H, D₂O exchangeable); MS m/z: 547.1 (M⁺+1).

The Following Compound was Made by the Procedure Mentioned Above

144

¹H-NMR (CDCl₃) δ: 1.98 (s, 3H), 2.17 (s, 3H), 2.19 (s, 3H), 7.05 (d,1H), 7.14 (m, 4H), 7.20-7.22 (m, 2H), 7.30-7.32 (m, 2H), 7.33 (d, 2H),8.55-8.56 (d, 2H), 8.69 (br, 1H, D₂O exchangeable); MS m/z: 594.1 (M⁺ +1).

Example 145 Synthesis of1-(2,6-dichlorophenyl)-3-{1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-t-butyl-1H-pyrazol-5-yl}urea

The solution of3-t-butyl-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrazol-5-amine(0.23 mmol) in dichloromethane (3 ml) was treated with2,6-dichlorophenyl isocyanate (0.056 g, 0.3 mmol) in the presence oftriethylamine (0.05 ml), and the reaction was mixture was stirred atroom temperature, overnight. Subsequently water (15 ml) was added toabove and it was extracted with ethyl acetate (25 ml). The organic layerwas evaporated and the crude material purified by column chromatography;elution with 1.5% of ethyl acetate in hexane yielded the title compound.¹H-NMR (CDCl₃) δ: 0.86 (s, 9H), 6.58 (s, 1H), 7.02-7.05 (m, 3H), 7.14(d, 2H), 7.24-7.33 (m, 8H), 8.43-8.44 (br, 1H, D₂O exchangeable), 10.52(br, 1H, D₂O exchangeable); MS m/z: 625 (M⁺).

Example 146 Synthesis of4-[4-(methylthio)phenyl]-5,6-diphenyl-2-(trifluoromethyl)pyrimidine

4-Chloro-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.2 g, 0.6 mmol,prepared according to the procedure described in PCT/IB03/02879) washeated to reflux with tetra-kis triphenyl palladium (0) (0.068 g, 0.058mmol), aqueous solution of potassium carbonate (0.16 g in 0.6 ml water),4-(methylthio)benzene boronic acid (0.168 g, 1 mmol) and toluene (20 ml)under a nitrogen atmosphere overnight. The reaction mixture wasacidified with dilute hydrochloric acid 10 ml and extracted with ethylacetate. The organic layer was concentrated; the crude material obtainedwas triturated with ether and filtered to yield the title compound.¹H-NMR (DMSO-d₆) δ: 2.45 (s, 3H), 7.13-7.15 (m, 4H), 7.23-7.34 (m, 8H),7.61 (d, 2H); MS m/z: 423.1 (M⁺+1).

The Following Compound was Prepared by the Above-Mentioned Procedure

147

¹H-NMR (DMSO-d₆) δ: 2.45 (s, 3H), 3.22 (s, 3H), 7.15-7.18 (m, 4H),7.26-7.34 (m, 5H), 7.52-7.54 (d, 2H), 7.83-7.85 (d, 2H); MS m/z: 501(M⁺ + 1).

Described below are the pharmacological assays used for finding out theefficacy of the compounds of the present invention.

In Vitro Evaluation of Cyclooxygenase-2 (COX-2) Inhibition Activity

The compounds of this invention exhibited in vitro inhibition of COX-2.The COX-2 inhibition activities of the compounds illustrated in theexamples were determined by the following method.

Human Whole Blood Assay

Human whole blood provides a protein and cell rich milieu appropriatefor the study of the biochemical efficacy of anti-inflammatory compoundssuch as selective COX-2 inhibitors. Studies have shown that normal humanblood does not contain the COX-2 enzyme. This correlates with theobservation that COX-2 inhibitors have no effect on prostaglandin E₂(PGE₂) production in normal blood. These inhibitors were active onlyafter incubation of human blood with lipopolysaccharide (LPS), whichinduces COX-2 production in the blood.

Fresh blood was collected in tubes containing sodium heparin by veinpuncture from healthy male volunteers. The subjects should have noapparent inflammatory conditions and should have not taken NSAIDs for atleast 7 days prior to blood collection. Blood was preincubated withaspirin in vitro (12 μg/ml, at time zero) to inactivate COX-1 for 6hours. Then test compounds (at various concentrations) or vehicle wereadded to blood, the blood was stimulated with LPS B:4 (10 μg/ml) andincubated for another 18 hours at 37° C. water bath. After which theblood was centrifuged, plasma was separated and stored at −80° C. (J.Pharmacol. Exp. Ther, 271, 1705, 1994; Proc. Natl. Acad. Sci. USA, 96,7563, 1999). The plasma was assayed for PGE₂ using Cayman ELISA kit asper the procedure outlined by the manufacturer (Cayman Chemicals, AnnArbor, USA). Representative results of PGE-2 inhibition are shown in theTable I.

TABLE I % PGE-2 Inhibition in hWBA Ex. 0.25 μM 1 μM 10 μM 4 6.10 22.8535.63 7 26.17 1.90 NA 22 15.64 20.40 36.37Wherein, NA indicates No activity and ND indicates Not Done.

COX-1 and COX-2 Enzyme Based Assay

COX-1 and COX-2 enzyme based assays were carried out to check theinhibitory potential of the test compounds on the production ofprostaglandin by purified recombinant COX-1/COX-2 enzyme (Proc. Nat.Acad. Sci. USA, 88, 2692-2696, 1991; J. Clin. Immunoassay 15, 116-120,1992). In this assay, the potential of the test compound to inhibit theproduction of prostaglandin either by COX-1 or COX-2 from arachidonicacid (substrate) was measured. This was an enzyme based in-vitro assayto evaluate selective COX inhibition with good reproducibility.

Arachidonic acid was converted to PGH₂ (Intermediate product) byCOX1/COX-2 in the presence or absence of the test compound. The reactionwas carried out at 37° C. and after 2 minutes it was stopped by adding1M HCl. Intermediate product PGH₂ was converted to a stable prostanoidproduct PGF_(2α) by SnCl₂ reduction. The amount of PGF_(2α) produced inthe reaction was inversely proportional to the COX inhibitory potentialof the test compound. The prostanoid product was quantified via enzymeimmunoassay (EIA) using a broadly specific antibody that binds to allthe major forms of prostaglandin, using Cayman ELISA kit as per theprocedure outlined by the manufacturer (Cayman Chemicals, Ann Arbor,USA). Representative results of inhibition are shown in the Table II.

TABLE II % Inhibition in rEnzyme Assay COX-1 COX-2 Ex. 1 μM 10 μM 1 μM10 μM 2 33.84 50.41 17.31 48.9 51 8.27 7.1 NA 12.29 53 46.29 56.85 20.0426.70 54 34.42 45.53 NA 13.71 57 NA 5.7 8.29 0.66 58 10.22 9.59 11.242.62 59 — 32 — 31 80 — NA — 20 116 6.29 19.24 NA 7.03

In Vitro Measurement of TNF-α in Human Peripheral Blood MononuclearCells

This assay determines the effect of test compounds on the production ofTNF a in human Peripheral Blood Mononuclear Cells (PBMC). Compounds weretested for their ability to inhibit the activity of TNF α in human PBMC.PBMC were isolated from blood (of healthy volunteers) using BDVacutainer CPT™ (Cell preparation tube, BD Bio Science) and suspended inRPMI medium (Physiol. Res. 52, 593-598, 2003). The test compounds werepre-incubated with PBMC (0.5 million/incubation well) for 15 minutes at37° C. and then stimulated with Lipopolysaccharide (Escherichia coli:B4; 1 μg/ml) for 18 hours at 37° C. in 5% CO₂. The levels of TNF-α inthe cell culture medium were estimated using enzyme-linked immunosorbentassay performed in a 96 well format as per the procedure of themanufacturer (Cayman Chemical, Ann Arbor, USA). Representative resultsof TNF-α inhibition are shown in the Table IIIa.

TABLE IIIa TNF-α Inhibition (%) at Ex. Conc. (1 μM) Conc. (10 μM) 429.98 107.36 5 35.86 56.34 11 12.71 50.71 12 34.81 78.42 13 25.77 35.2714 25.47 67.54 24 53.86 32.91 25 38.77 94.02 26 32.70 50.79 27 43.4951.92 30 43.23 100 31 37.39 62.48 34 NA 80.88 35 17.13 86.57 36 51.2626.92 55 81.46 91.61 57 84.50 88.86 59 87 92 80 50 78 98 94.1 94.6 11637.84 58.28 66 57.85 80.68 118 69.71 86.49 120 88.92 91.50 158 33.591.31

In Vitro Measurement of TNF-α in Human Whole Blood

This assay determines the effect of test compounds on the production ofTNF-α in human whole blood. Compounds were tested for their ability toinhibit the activity of TNF-α in whole blood.

Heparanised blood from a healthy human volunteer was collected anddiluted with RPMI 1640 incomplete medium (1:5 dilution). Diluted bloodwas aliquoted into 96 well plate 170 ul/well immediately. 20 ul of thedrug of different concentrations was added to the respective wells witha control. The plate was incubated in 37° C. thermo mixer at 400 rpm for60-70 minutes. After the incubation 10 ul of the LPS (from E. coli B4)was added to get the final concentration of 1 ug/well. The plate wasagain incubated in the 37° C. thermo mixer at 400 rpm 120 minutes in thethermo mixer and then left in the 37° C. CO₂ incubator for two morehours so that the total stimulation time is four hours. The plasma wascollected carefully without disturbing the pellet at the bottom andstored at −20° C. Then TNF-α levels were estimated using the R&D systemsELISA kit duoset kit (DY210). Representative results of TNF-α inhibitionare shown in the Table IIIb.

TABLE IIIb TNF-α Inhibition (%) at Ex. Conc. (1 μM) Conc. (10 μM) 9840.6 62.0

In Vitro Measurement of Interleukin-6 (IL-6)

This assay determines the effect of test compounds on the production ofIL-6 in human PBMC (Physiol. Res. 52, 593-598, 2003). Compounds weretested for their ability to inhibit the activity of IL-6 in human PBMC.PBMC were isolated from blood using BD Vacutainer CPT™ Cell preparationtube (BD Bio Science) and suspended in RPMI medium. The test compoundswere pre-incubated with PBMC (0.5 million/incubation well) for 15minutes at 37° C. and then stimulated with Lipopolysaccharide(Escherichia coli: B4; 1 μg/ml) for 18 hours at 37° C. in 5% CO₂. Thelevels of IL-6 in cell culture medium were estimated using enzyme-linkedimmunosorbent assay performed in a 96 well format as per the procedureof the manufacturer (Cayman Chemical, Ann Arbor, USA). Representativeresults of inhibition are shown in the Table IV.

TABLE IV IL-6 Inhibition (%) Ex. Conc. (1 μM) Conc. (10 μM) 4 27.17 10018 32.83 41.04 19 27.88 41.91 59 26.14 36.82 61 24.51 54.49 78 22.2825.26 80 — NA 158 — 65.71

TABLE V IL-12 inhibition IL-12 Inhibition (%) Ex. Conc. (1 μM) Conc. (10μM) 158 69.03 98.26

Carrageenan Induced Paw Edema Test in Rat

The carrageenan paw edema test was performed as described by Winter etal (Proc. Soc. Exp. Biol. Med, 111, 544, 1962). Male wistar rats wereselected with body weights equivalent within each group. The rats werefasted for 18 hours with free access to water. The rats were dosedorally with the test compound suspended in the vehicle containing 0.25%carboxymethylcellulose and 0.5% Tween 80. The control rats wereadministered with vehicle alone. After an hour, the rats were injectedwith 0.1 ml of 1% Carrageenan solution in 0.9% saline into thesub-plantar surface of the right hind paw. Paw volume was measured usingdigital plethysmograph before and after 3 hours of carrageenaninjection. The average of foot swelling in drug treated animals wascompared with that of the control animals. Anti-inflammatory activitywas expressed as the percentage inhibition of edema compared withcontrol group (Arzneim-Forsch/Drug Res., 43 (I), 1, 44-50, 1993);Representative results of edema inhibition are shown in the Table VI.

TABLE VI Ex. Inhibition of edema (%) at 5 mg/kg 4 17.12 5 14.5

Ulcerogenic Potential

In order to evaluate the compound's role on the ulcer formation, theanimals were sacrificed and the stomach was taken out and flushed with1% formalin. Animals (male wistar 200 g) were fasted for 18 hours withfree access to water and the test compounds were suspended in 0.5% Tween80 and 0.25% CMC (carboxymethylcellulose) solution to make a uniformsuspension. After 4 hours of oral administration of test compounds, allthe animals were sacrificed by cervical dislocation. The stomach wasdissected carefully and filled up with a sterile saline solution andembedded in 6% formalin solution. Finally the stomach was cutlongitudinally and ulcer lesions were observed with computerizedstereomicroscope. The test compound treated groups were compared withthe vehicle treated groups. Doses selected: 50, 100, 200 mg/kg (MarcoRomano et al, Journal of clinical Investigation, 1992; 2409-2421.)Representative results of ulcer incidence are shown in the Table VII

TABLE VII Ex. Ulcer incidence at 5 mg/kg 4 Nil 5 Nil

Inhibitory Action on Adjuvant Arthritis in Rats

Compounds were assayed for their activity on rat adjuvant inducedarthritis model according to Theisen-Popp et al., (Agents Actions, 42,50-55, 1994). 6 to 7 weeks old, wistar rats were weighed, marked andassigned to groups [a negative control group in which arthritis was notinduced (non-adjuvant control), a vehicle-treated arthritis controlgroup, test substance treated arthritis group]. Adjuvant inducedarthritis was induced by an injection of 0.1 ml of Mycobacteriumbutyricum (Difco) suspended in mineral oil (5 mg/ml) into thesub-plantar region of the right hind paw (J. Pharmacol. Exp. Ther., 284,714, 1998). Body weight, and paw volumes were measured at various days(0, 4, 14, 21) for all the groups. The test compound or vehicle wasadministered orally, beginning post injection of adjuvant (‘0’ day) andcontinued for 21 days (pre-treatment group). In the post-treatmentgroup, the test compound or vehicle was administered starting from day14^(th) to 21^(st) day. On day 21, body weight and paw volume of bothright and left hind paws were taken. Spleen, and thymus weights weredetermined. In addition, the radiographs of both hind paws were taken toassess the tibio-tarsal joint integrity. Hind limb below the stiflejoint was removed and fixed in 1% formalin saline for thehistopathological assessment. At the end of the experiment, serumsamples were analyzed for inflammatory mediators. The presence orabsence of lesions in the stomach was also observed.

Two-factor (‘treatment’ and ‘time’) analysis of variance with repeatedmeasures on ‘time’ was applied to the percentage (%) changes for bodyweight and foot volumes. A post hoc Dunnett's test was conducted tocompare the effect of treatments to vehicle control. A one-way analysisof variance was applied to the thymus and spleen weights followed by theDunnett's test to compare the effect of treatments to vehicle.Dose-response curves for percentage inhibition in foot volumes on days4, 14 and 21 were fitted by a 4-parameter logistic function using anonlinear least Squares regression. IC₅₀ was defined as the dosecorresponding to a 50% reduction compared to the vehicle control and wasderived by interpolation from the fitted 4-parameter equation.

LPS Induced Sepsis for Measurement of TNF-α Inhibition in Mice

The LPS induced sepsis model in mice was performed as described by Lessekut et al (J Lab Clin Med 1994; 124, 813-20). Female Swiss albino micewere selected and the body weights were equivalent within each group.The mice were fasted for 20 hours with free access to water. The micewere dosed orally with the test compound suspended in vehicle containing0.5% Tween 80 in 0.25% Carboxy-methylcellulose sodium salt. The controlmice were administered the vehicle alone. After 30 minutes of oraldosing, mice were injected with 500 μg of Lipopolysaccharide(Escherichia coli, LPS: B4 from Siga) in phosphate buffer salinesolution into the intraperitoneal cavity of the mice. After 90 minutesof LPS administration mice were bled via retro-orbital sinus puncture.Blood samples were stored overnight at 4° C. Serum samples werecollected by centrifuging the samples at 4000 rpm for 15 minutes at 4°C. Immediately the serum samples were analyzed for TNF-α levels usingcommercially available mouse TNF-α ELISA kit (Amersham Biosciences) andassay was performed by the manufacturer instruction. Representativeresults of TNF-α inhibition are shown in the Table VIII.

TABLE VIII Ex. TNF-α Inhibition (%) at 50 mg/kg 4 38.37 30 84.84 3559.62 53 70.93 54 63.44 57 52.02 59 87.15 80 82.75 116 54.23

ED₅₀ Measurement of TNF Alpha Inhibition in Mice Sepsis Model

TABLE IX Ex. Mice Sepsis ED50 mg/kg 80 2.13 98 0.01

Inhibitory Activity in IBD-DSS Model

DSS Induced colitis test was performed as described by Axelsson et al.,1998. Male Balb/c mice were selected in the age of 7-8 weeks for thestudy. Colitis in mice was induced by providing DSS (2%) in the drinkingwater from day 1 to 6. Mice were dosed from Day 1 to 6 with testcompound suspended in vehicle containing 0.25% carboxymethyl celluloseand 0.5% Tween 80. The control animals received vehicle alone. Bodyweight and disease activity index was recorded daily during theexperiment. After 6 days of treatment, animals were sacrificed; colonweight and colon length was recorded. Representative results are shownin the table X.

TABLE X IBD-DSS Model % Inhibition of Ex. DAI at 50 mg/kg 80 35.94

Inhibitory Activity in Psoriasis Model

Oxazolone induced dermatitis in mice was performed as described in theliterature. Female Balb/c were selected in the age of 6-7 weeks for thestudy and 20-25 g. Mice were sensitized with oxazolone (15%) from Day 1to day 6 by applying it on the shaved abdomen. Elicitation was done withoxazolone (2%) on the ear on day 7. Test compounds were appliedtopically on the ear 15 minutes and 6 hours post oxazolone applicationon day 7. 24 hours after oxazolone application, ear thickness ismeasured and ear were excised under anesthesia and weighed.Representative results are shown in table XI.

TABLE XI Psoriasis-acute- Oxazolone induced dermatitis % inhibition Ex.Ear Wt Ear Thick 80 18.9 19.2

Inhibitory Activity in Psoriasis Model

TPA induced dermatitis in mice was performed using the protocoldescribed in Eur J Pharmacol 507, 253-259, 2005. Balb/c mice wereacclimatized to laboratory conditions 5-7 days prior to the start of theexperiment. They were randomly distributed to various groups based onbody weight. The baseline ear thickness of the animal's both ears usingthickness gauge was measured. For each animal 20 μl of that contains 2.5μg of TPA was applied with help of micropipettor with disposable tips.Test compound was applied topically to both inner and outer surface ofthe both the ears i.e. left and right ear with acetone as control after30 minutes 6 hours and 24 hours after application of TPA (20 μl). Earthickness was measured after 6 and 24 hours in animals, while for earweight ears were excised under anesthesia and weighed. Representativeresult are shown in the table

TABLE XI Psoriasis-acute TPA induced dermatitis % inhibition Ex Ear WtEar thickness 80 18.9 19.2 98 11.84 41.10

LPS Induced Neutrophilia Model for Asthma and COPD

LPS induced neutrophilia in Wistar rats was performed using the protocoldescribed in Pulm Pharmacol & Ther 17, 3, 133-140, 2004. Male Wistarrats were acclimatized to laboratory conditions five to seven days priorto the start of the experiment. They were randomly distributed tovarious groups based on body weight. Except normal group all the animalswere exposed to LPS 100 μg/ml for 40 min. The rats were dosed with thetest compound suspended in the vehicle containing 0.25%carboxymethylcellulose before half an hour of LPS exposure. BAL wasperformed 4 h after LPS exposure, total cell count and DLC was done andcompared with control and the standard drug. Percentage Inhibition forneutrophilia was calculated.

TABLE XII LPS induced neutrophilia Ex % inhibition at 10 mg/kg 98 31.73

Anti-Cancer Screen

Experimental drugs are screened for anti-cancer activity in three celllines for their GI₅₀, TGI and LC₅₀ values (using 5 concentrations foreach compound). The cell lines are maintained in DMEM containing 10%fetal bovine serum. 96 well microtiter plates are inoculated with cellsin 100 μM for 24 hours at 37° C., 5% CO₂, 95% air and 100% relativehumidity. 5000 HCT116 cells/well, 5000 NCIH460 cells/well, 10000 U251cells/well and 5000 MDAMB231 cells/well are plated. A separate platewith these cell lines is also inoculated to determine cell viabilitybefore the addition of the compounds (T₀).

Addition of Experimental Drugs

Following 24-hour incubation, experimental drugs are added to the 96well plates. Each plate contains one of the above cell lines and thefollowing in triplicate: 5 different concentrations (0.01, 0.1, 1, 10and 100 μM) of 4 different compounds, appropriate dilutions of acytotoxic standard and control (untreated) wells. Compounds aredissolved in dimethylsulfoxide (DMSO) to make 20 mM stock solutions, onthe day of drug addition and frozen at −20° C. Serial dilutions of these20 mM stock solutions are made in complete growth medium such that 100μL of these drug solutions in medium, of final concentrations equaling0.01, 0.1, 1, 10 and 100 μM can be added to the cells in triplicate.Standard drugs whose anti-cancer activity has been well documented andwhich are regularly used are doxorubicin and SAHA.

End-Point Measurement

Cells are incubated with compounds for 48 hours followed by the additionof 10 μL 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium (MTT)solution per well and a subsequent incubation at 37° C., 5% CO₂, 95% airand 100% relative humidity, protected from light. After 4 hours, wellcontents are aspirated carefully followed by addition of 150 μL DMSO perwell. Plates are agitated to ensure solution of the formazan crystals inDMSO and absorbance read at 570 nm.

Calculation of GI₅₀, TGI and LC₅₀

Percent growth is calculated for each compound's concentration relativeto the control and zero measurement wells (T₀; viability right beforecompound addition). If a test well's O.D. value is greater than the T₀measurement for that cell line % Growth=(test−zero)/(control−zero)×100

If a test well's O.D. value is lower than the T₀ measurement for thatcell line, then: % Growth=(test−zero)/zero×100

Plotting % growth versus experimental drug concentration, GI₅₀ is theconcentration required to decrease % growth by 50%; TGI is theconcentration required to decrease % growth by 100% and LC₅₀ is theconcentration required to decrease % growth by 150%. Representativeresults of growth are shown in the Table XIII.

TABLE XIII GI₅₀ (μM) Ex. DU-145 HCT-116 NCI-H460 2 3.5 2.5 8.5 4 1.93 21.65 38 4 6 3.75 40 ND 3.5 3.8 41 ND 7 4 44 ND 26 4.5 51 ND 30 4.0 59ND >100 10.5 73 ND 9.2 9.0 80 ND >100 >100 144 ND 20 0.1

PDE4 Activity

PDE4 inhibition was measured by following a literature assay procedure(Cortizo J et al., Br J. Pharmacol., 1993, 108: 562-568. The assaymethod involves the following conditions.

Source: Human U937 cellsSubstrate: 1.01 μM [³H] camp+camp

Vehicle: 1% DMSO

Pre-Incubation Time/Temperature: 15 minutes at 25° C.Incubation Time/Temperature. 20 minutes at 25° C.Incubation buffer: 50 mM Tris-HCl, pH 7.5, 5 mM MgCl₂Quantitation method: Quantitation of [³H] AdenosineSignificance criteria: ≧50% of max stimulation or inhibitionThe results are tabulated as shown in the tables XIVa and XIVb.

TABLE XIVa Ex. PDE4 inhibition at 10 μM (%)  59 93  77 94  80 87  98*76.1 109 90 100 92 167 82 173 87 175 88 179 84 * In this case assay isdone with pure PDE4B enzyme (Calbiochem)

TABLE XIVb Ex PDE4 inhibition IC50 (nm) 98 7

The Tables XVA and XVB Contain The Disclosed Compounds That Show TheCommon Inhibitory Effects on PDE4 Inhibitors, TNF-α, IL-12, and IL-6etc.,

TABLE XVa TNF -α COX1 COX2 IL-1β IL-6 IL-12 TNF- α in vivo at at at atat Ex IC₅₀ nm (mice) 10 μm 10 μm 10 μm 10 μm 10 μm 80 78 87 NA 20 36 NAND 59 64 82 32 31 29 37 ND

TABLE XVb Cancer cell lines DU, PDE4 at IBD Psoriasis HCT, NCI (MeanGI50, Ex 10 μm Arthritis DAI Ear thickness μm) 80 93 ND 35 19 >100 (forHCT and NCI) 59 87 ND ND ND >100 (for HCT); 10.5(for NCI)

1. Novel compounds of the general formula (I),

their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs,solvates, pharmaceutically acceptable salts and compositions,metabolites and prodrugs thereof, wherein A represents substituted orunsubstituted aryl group; B represents substituted or unsubstitutedgroups selected from aryl or pyridyl; X represents carbon or nitrogenatom; R represents substituted or unsubstituted groups selected fromazido; halogens; linear or branched alkyl groups comprising methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl,isopentyl and hexyl; alkoxy groups comprising methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy; haloalkylgroups comprising dichloromethyl, difluoromethyl, trifluoromethyl andtrichloromethyl; acyl groups comprising acetyl and propanoyl; cycloalkylgroups comprising cyclopropyl, cyclobutyl and cyclopentyl; amino;hydrazine; monoalkylamino; dialkylamino; acylamino groups comprisingacetylamino and propanoylamino; alkylsulfonyl groups comprisingmethylsulfonyl, ethylsulfonyl and propylsulfonyl; alkylsulfinyl;arylsulfonyl; arylsulfinyl; alkoxycarbonyl comprising methoxycarbonyland ethoxycarbonyl; aryloxycarbonyl; alkoxyalkyl; sulfamoyl; aryl groupscomprising phenyl and naphthyl; heteroaryl groups comprising pyridyl,thienyl, furyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyrazinyl,benzofuranyl, benzimidazolyl and benzothiazolyl; aryloxy; —OSO₂R′ andheterocyclyl groups comprising morpholine, thiomorpholine, piperazine,piperidine, piperidin-4-one, pyrrolidine, pyrrol-2,5-dione,thiazolidine, 1-oxido-thiazolidine and 1,1-dioxido-1,3-thiazolidine; theheterocyclyl group is optionally substituted with substitutentsindependently selected from substituted or unsubstituted alkyl, aryl,heteroaryl, aralkyl (—CH₂-aryl), alkylheteroaryl (—CH₂-heteroaryl),substituted arylcarbonyl (—CO—Ar), heteroarylcarbonyl (—CO-heteroaryl),heteroarylthiocarbonyl (—CS-heteroaryl), cycloalkylcarbonyl(—CO-cycloalkyl), cyanoalkyl, —O-methyloxime, alkylsulfonyl,haloalkylsulfonyl, haloacyl, —SO₂Cl, formyl, hydroxamic acid and anothersubstituted or unsubstituted heterocyclyl group; the attachment of theheterocyclyl group to the pyrimidine ring is through carbon or nitrogen;wherein R′ represents substituted or unsubstituted groups selected fromalkyl, aryl, alkyldialkylamino, haloalkyl, heterocyclyl and heteroarylgroups; R₁ represents hydrogen; hydroxy; nitro; formyl; azido; halogens;substituted or unsubstituted groups selected from alkyl; haloalkyl;alkoxy; aryl; aryloxy groups selected from phenoxy and naphthoxy;acyloxy groups comprising MeCOO—, EtCOO— and PhCOO—; amino; hydrazine;monoalkylamino; dialkylamino; acylamino; alkylsulfonyl; alkylsulfinyl;alkylthio; alkoxycarbonyl; alkoxyalkyl; sulfamoyl; —SO₂NHNH₂; —SO₂Cl;carboxylic acid and its derivatives; R₂ represents hydrogen; hydroxy;nitro; formyl; azido; halogens; substituted or unsubstituted groupsselected from alkyl; haloalkyl; alkoxy; aryl; aryloxy; acyloxy; amino;hydrazine; monoalkylamino; dialkylamino; acylamino; alkylsulfonyl;alkylsulfinyl; alkylthio; alkoxycarbonyl; alkoxyalkyl; sulfamoyl;—SO₂NHNH₂; —SO₂Cl; carboxylic acid and its derivatives; R₃ representshydrogen; hydroxy; nitro; formyl; azido; halogens; substituted orunsubstituted groups selected from alkyl; haloalkyl; alkoxy; aryl;aryloxy; acyloxy; amino; hydrazine; monoalkylamino; dialkylamino;acylamino; alkylsulfonyl; alkylsulfinyl; alkylthio; alkoxycarbonyl;alkoxyalkyl; sulfamoyl; —SO₂NHNH₂; —SO₂Cl; carboxylic acid and itsderivatives; R₄ represents hydrogen; hydroxy; nitro; formyl; azido;halogens; substituted or unsubstituted groups selected from alkyl;haloalkyl; alkoxy; aryl; aryloxy; acyloxy; amino; hydrazine;monoalkylamino; dialkylamino; acylamino; alkylsulfonyl; alkylsulfinyl;alkylthio; alkoxycarbonyl; alkoxyalkyl; sulfamoyl; —SO₂NHNH₂; —SO₂Cl;carboxylic acid and its derivatives; R, R₁, R₂, R₃, R₄ and R′ groups areoptionally substituted by one or more substituents selected fromhalogens; hydroxy; nitro; cyano; ureas; azido; amino; imino-1-phenylbutanone; amide groups such as acetamide, benzamide and the like;thioamide; hydrazine; linear or branched alkyl groups comprising methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl,isopentyl and hexyl; alkoxy groups comprising methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy; haloalkylgroups comprising dichloromethyl, difluoromethyl, trifluoromethyl andtrichloromethyl; acyl groups comprising acetyl, propanoyl and benzoyl;haloalkoxy groups comprising trifluoromethoxy, trifluoroethoxy,trichloromethoxy; cycloalkyl groups comprising cyclopropyl andcyclobutyl; haloacyl groups comprising trifluoroacetyl andtrichloroacetyl; acyloxyacyl; heterocyclyl; aryl; heteroaryl;monoalkylamino; dialkylamino; acylamino; aryloxy groups comprisingphenoxy and naphthoxy; alkoxycarbonyl groups comprising methoxycarbonyland ethoxycarbonyl; aryloxycarbonyl; alkylsulfonyl; haloalkylsulfonyl;—SO₂Cl; arylsulfonyl; alkylsulfinyl; arylsulfinyl; thioalkyl; thioaryl;sulfamoyl; alkoxyalkyl groups; carboxylic acids and its derivativescomprising hydroxamic acids; hydroxamates; esters; amides and acidhalides, these substituents are further optionally substituted withsubstituents selected from hydroxy; alkoxy; halogens; alkylsulfonyl;haloalkyl; alkyl and aryl group which in turn is optionally furthersubstituted by halogens and alkyl.
 2. A compound of formula (I) asdefined in claim 1 selected from the compounds consisting of:N-({4-[4-Amino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl]phenyl}sulfonyl)acetamide;4-{4-Amino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}-N-methylbenzenesulfonamide;4-{4-Chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonylchloride;4-{4-Chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}-N-methylbenzenesulfonamide;4-{4-(Methylamino)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}-N-methylbenzenesulfonamide;N-[(4-{4-(Methylamino)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}phenyl)sulfonyl]acetamide;4-{4-Hydrazino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonohydrazide;4-[4-(4-Fluorophenyl)-6-hydrazino-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonohydrazide;N-[(4-{4-Hydrazino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl)phenyl}sulfonyl]acetamide;4-{4-Hydrazino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimdin-5-yl}-N-methylbenzenesulfonamide;4-Hydrazino-5-phenyl-6-pyridin-3-yl-2-(trifluoromethyl)pyrimidine;4-Hydrazino-5-phenyl-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidine;5-(4-Fluorophenyl)-4-hydrazino-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidine;2,2,2-Trifluoro-N-[5-(4-fluorophenyl)-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidin-4-yl]acetohydrazide;N′-[5-Phenyl-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidin-4-yl]acetohydrazide;2,2,2-Trifluoro-N-[5-phenyl-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidin-4-yl]acetohydrazide;N-[(4-{4-Chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}phenyl)sulfonyl]acetamide;6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-ylnapthalenesulfonate;6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-3-chloropropane-1-sulfonate;6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-3-(trifluoromethyl)benzenesulfonate;6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-2-(trifluoromethyl)benzenesulfonate;6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-4-methylbenzenesulfonate;6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-4-nitrobenzenesulfonate;6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-4-trifluoromethoxybenzenesulfonate;6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-ylthiophene-2-sulfonate;6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-4-fluorobenzenesulfonate;6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-2-fluorobenzenesulfonate;6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-(dimethylamino)propanesulfonate;6-[4-(Methylsulfonyl)phenyl]-5-phenyl-4-(N-benzyl-piperazin-1-yl)-2-(trifluoromethyl)pyrimidine;4-[4-(4-Fluorophenyl)-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;4-[5-(4-Fluorophenyl)-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide;N-Methyl-4-[4-(methylsulfonyl)phenyl]-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;4-[4-(Methylsulfonyl)phenyl]-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;4-{4-(Morpholin-4-yl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}-N-methylbenzenesulfonamide;5-{4-[4-(Methylsulfonyl)phenyl]-6-piperidin-1-yl-2-(trifluoromethyl)pyrimidin-5-yl}-N-methylbenzenesulfonamide;4-[4-(Methylsulfonyl)phenyl]-6-[4-[(5-methylpyrazin-2-yl)carbonyl]piperazin-1-yl]-5-phenyl-2-(trifluoromethyl)pyrimidine;6-[4-(Methylsulfonyl)phenyl]-5-phenyl-4-{4-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperazin-1-yl}-2-(trifluoromethyl)pyrimidine;6-[4-(Methylsulfonyl)phenyl]-4-[4-(5-nitro-2-furoyl)piperazin-1-yl]-5-phenyl-2-(trifluoromethyl)pyrimidine;N-Methyl-4-{4-[4-(5-nitro-2-furoyl)piperazin-1-yl]-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;4-{5-[4-Fluorophenyl]-4-[4-(5-nitro-2-furoyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-6-yl}benzenesulfonamide;4-{6-[4-Fluorophenyl]-4-[4-(5-nitro-2-furoyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;6-[4-(Methylsulfonyl)phenyl]-4-{4-[(5-nitro-1H-pyrazol-3-yl)carbonyl]piperazin-1-yl}-5-phenyl-2-(trifluoromethyl)pyrimidine;5,6-Diphenyl-4-[4-(5-nitro-2-furoyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidine;5-[4-Fluorophenyl]-4-[4-(5-nitro-2-furoyl)piperazin-1-yl]-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidine;6-[4-(Methylsulfonyl)phenyl]-5-phenyl-4-[4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidine;4-[4-(Methylsulfonyl)phenyl]-5-phenyl-6-[4-(pyridin-4-ylmethyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidine;6-[4-(Methylsulfonyl)phenyl]-4-{4-[(5-nitro-2-thienyl)methyl]piperazin-1-yl}-5-phenyl-2-(trifluoromethyl)pyrimidine;4,5-Diphenyl-6-(4-pyridin-2-yl-piperazin-1-yl)-2-(trifluoromethyl)pyrimidine;4-[4-(Methylsulfonyl)phenyl]-5-phenyl-6-(4-pyridin-2-yl-piperazin-1-yl)-2-(trifluoromethyl)pyrimidine;3-[4-(4-Fluorophenyl)-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[4-Phenyl-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[5-(3-Aminosulfonylphenyl)]-6-piperazin-1-yl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide;3-[4-(4-Fluorophenyl)-6-(4-pyridin-2-ylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[4-(4-Fluorophenyl)-6-(4-pyrimidin-2-ylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[5-Phenyl-6-(1,3-thiazolidin-3-yl)-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide;3-[6-[(4-Hydroxycyclohexyl)amino]-5-(3-aminosulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide;3-[6-(4-Pyrimidin-2-ylpiperazin-1-yl)]-4-phenyl-2-(trifluoromethyl)pyrimidin-5-ylbenzenesulfonamide;3-[6-(4-Pyridin-2-ylpiperazin-1-yl)]-4-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;Ethyl-1-[5-(3-aminosulfonylphenyl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl]piperidine-4-carboxylate;3-[4-[(4-Hydroxycyclohexyl)amino]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;Ethyl1-[6-phenyl-5-(3-aminosulfonylphenyl)1-2-(trifluoromethyl)pyrimidin-4-yl]piperidine-4-carboxylate;4-[6-Phenyl-5-(3-morpholinosulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]morpholine;3-[4-(4-Fluorophenyl)-6-morpholin-4-yl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;(3R)-1-[6-(4-Fluorophenyl)-5-(3-aminosulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]pyrrolidin-3-ol; Ethyl(2S,4R)-4-hydroxy-1-[6-(4-fluorophenyl)-5-(3-aminosulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]pyrrolidine-2-carboxylate;4-[4-(2,6-Dimethoxypyrimidin-4-yl)piperazin-1-yl]-5-(3-aminosulfonylphenyl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidine;5-(4-Fluorophenyl)-4-(4-pyridin-2-ylpiperazin-1-yl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidine;4-(4-Methylsulfonylphenyl)-5-(4-fluorophenyl)-6-(4-pyrimidin-2-ylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidine;4-[5-(4-Fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-4-yl]piperazine-1-carbaldehyde;1′-[5-(4-Fluorophenyl)-6-(4-methylsulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]-1,4′-bipiperidine;3-[4-(4-Fluorophenyl)-6-(1,4′-bipiperidin-1′-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[4-(2-Furoyl)piperazin-1-yl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;5-(3-Aminosulfonylphenyl)-4-(4-fluorophenyl)-2-(trifluoromethyl)-6-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}pyrimidine;5-(4-Fluorophenyl)-4-(4-methylsulfonylphenyl)-2-(trifluoromethyl)-6-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}pyrimidine;3-[4-(4-Fluorophenyl)-6-(1,3-thiazolidin-3-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;1-[5-[3-(Aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl]pyrrolidine-2-carboxamide;5-(3-Aminosulfonylphenyl)-4-(4-fluorophenyl)-2-(trifluoromethyl)-6-{4-[(trifluoromethyl)sulfonyl]piperazin-1-yl}pyrimidine;3-[4-[4-(Methylsulfonyl)piperazin-1-yl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[4-[4-(Cyanomethyl)piperazin-1-yl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[4-(4-Fluorophenyl)-6-(1H-imidazol-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;5-(6-(4-Fluorophenyl)-4-(1H-imidazol-1-yl)-6-[4-(methylsulfonyl)phenyl]2-(trifluoromethyl)pyrimidine;N-({3-[6-(4-Fluorophenyl)-4-(4-pyridin-2-ylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]phenyl}sulfonyl)propanamide;3-[6-(4-Fluorophenyl)-4-(morpholin-4-yl)-2-(trifluoromethyl)pyrimidin-5-yl]-N-cyclopropylbenzenesulfonamide;3-[6-(4-Fluorophenyl)-4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[6-(4-Fluorophenyl)-4-(2-methyl-5-nitro-1H-imidazol-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[6-(4-Fluorophenyl)-4-(4-oxopiperidin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[4-(Cyclopropylamino)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[6-(4-Fluorophenyl)-4-(4-phenyl-1H-imidazol-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[6-(4-Fluorophenyl)-4-(2,6-dimethylmorpholin-4-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[6-(4-Fluorophenyl)-4-(2,6-dimethylpiperazin-4-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[6-(4-Fluorophenyl)-4-(2-methylpiperazin-4-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[6-(4-Fluorophenyl)-4-(1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[6-(4-Fluorophenyl)-4-(3-amino-1H-pyrazol-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[6-(4-Fluorophenyl)-4-(thiomorpholin-4-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[6-(4-Fluorophenyl)-4-({2-[(methylsulfonyl)amino]ethyl}amino)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-{6-(4-Fluorophenyl)-4-[3-methyl-4-(methylsulfonyl)piperazin-1-yl]-2-trifluoromethylpyrimidin-5-yl}benzenesulfonamide;3-{6-(4-Fluorophenyl)-4-[3-(hydroxymethyl)-4-(4-fluorophenyl)piperidin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;3-[4-Morpholin-4-yl-2-(trifluoromethyl)-6-phenyl-pyrimidin-5-yl]benzenesulfonamide.3-[6-(4-Fluorophenyl)-4-(2-morpholin-4-ylethoxy)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-{4-[4-(2-Cyanoethyl)piperazin-1-yl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;3-{6-(4-Fluorophenyl)-4-[3-methyl-4-(pyridin-2-yl-methyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;3-{6-(4-Fluorophenyl)-4-[3-methyl-4-(3-methoxybenzyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;3-(6-(4-Fluorophenyl)-4-[4-(pyridin-2-yl-methyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-ylbenzenesulfonamide;3-(6-(4-Fluorophenyl)-[4-(3-methoxybenzyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl)benzenesulfonamide;3-{6-(4-Fluorphenyl)-[4-(2-hydroxyethyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;3-(6-(4-Fluorophenyl)-4-[4-(1H-imidazol-1-ylcarbonothioyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl)benzenesulfonamide;3-[4-(1,1-Dioxido-1,3-thiazolidin-3-yl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[6-(4-Fluorophenyl)-4-(1-oxido-1,3-thiazolidin-3-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-{6-(4-Fluorophenyl)-4-[4-(trifluoroacetyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;3-{6-(4-Fluorophenyl)-4-[4-(2-fluorobenzoyl)piperazin-1-yl]-2-trifluoromethylpyrimidin-5-yl}benzenesulfonamide;4-{5-[3-(Aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}piperazine-1-sulfonylchloride;3-(4-[4-(Cyclopropylcarbonyl)piperazin-1-yl]-6-(4-fluorphenyl)-2-(trifluoromethyl)-pyrimidin-5-yl)benzenesulfonamide;3-{6-(4-Fluorophenyl)-4-[4-(methoxyimino)piperidin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;3-{6-(4-Fluorophenyl)-4-[(3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)amino]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;3-{4-[(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)amino]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;3-[6-{4-[5-(Trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-4-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide;3-[6-{4-[2,6-Dimethoxypyrimidin-4-yl]piperazin-1-yl}-4-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[6-{4-[5-(Nitro)pyridin-2-yl]piperazin-1-yl}-4-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[6-{4-[5-(Amino)pyridin-2-yl]piperazin-1-yl}-4-[4-fluorophenyl]-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;4-[5-(Acetylamino)pyridin-2-yl]piperazin-1-yl-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidine;N-({3-[4-Pyridin-2-yl]piperazin-1-yl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]phenyl}sulfonyl)acetamide;4-Fluorophenyl-5-(3-propionylaminosulfonylphenyl)-6-([4-pyridin-2-yl]piperazin-1-yl)-2-(trifluoromethyl)pyrimidine;1-{5-[3-(Aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}piperidine-4-carboxylicacid;4-[4-(Methoxyaminocarbonyl)piperidin-1-yl}-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidine;1-{5-[3-(Aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}-N-hydroxypiperidine-4-carboxamide;Methyl-3-methoxy-4-({6-[4-(methylsulfonyl)phenyl]-5-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}oxy)benzoate;3-Methoxy-4-({6-(4-fluorophenyl)-5-[3-(aminosulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-4-yl}oxy)-N-methoxybenzamide;4-{[5-(4-Fluorophenyl)-6(4-methylsulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}-N,3-dimethoxybenzamide;5-Amino-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-methyl-1H-pyrazole-4-carbonitrile;Ethyl-5-amino-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]3-(methylthio)-1H-pyrazole-4-carboxylate;5-Amino-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrazole-4-carbonitrile;3-t-Butyl-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrazol-5-amine;4-(3,5-Dimethyl-1H-pyrazol-1-yl)-5,6-diphenyl-2-(trifluoromethyl)pyrimidine;3-[4-(5-Amino-4-cyano-3-methyl-1H-pyrazol-1-yl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;Ethyl-5-amino-1-[5-[3-(aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-1H-pyrazole-4-carboxylate;4-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-6-[5-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidine;5-Amino-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrazole-4-carbothioamide;(3Z)-4,4,4-Trifluoro-1-phenylbutane-1,3-dione-3-{[5-phenyl-6-(4-methylsulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]hydrazone};N-{1-[5,6-Diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-t-butyl-1H-pyrazol-5-yl}-4-methoxybenzamide;N-{1-[5,6-Diphenyl-2-(trifluoromethyl)pyrimidin-4-yl}-3H-pyrazol-5-yl]-3-fluorobenzamide;N-{1-[5,6-Diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3H-pyrazol-5-yl}-4-(trifluoromethyl)benzamide;Ethyl-5-amino-1-[5-phenyl-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-1H-pyrazole-4-carboxylate;5-Amino-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-N-phenyl-1H-pyrazole-4-carboxamide;5-Amino-N-(4,5-dimethylphenyl)-1-[5-(4-fluorophenyl)-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-1H-pyrazole-4-carboxamide;1-(2,6-Dichlorophenyl)-3-{1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-t-butyl-1H-pyrazol-5-yl}urea;4-[4-(Methylthio)phenyl]-5,6-diphenyl-2-(trifluoromethyl)pyrimidine;5-Phenyl-4-[4-(methylsulfonyl)phenyl]-6-[4-(methylthio)phenyl]-2-(trifluoromethyl)pyrimidine;3-[4-(3,5-Dimethylpiperazin-1-yl)-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-{4-[(3S)-3-Methylpiperazin-1-yl]-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;3-[4-(2,6-Dimethylmorpholin-4-yl)-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;2,2,2-Trifluoro-N-({3-[6-phenyl-4-(4-(trifluoroacetyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]phenyl}sulfonyl)acetamide;3-[4-(2-Amino-1H-imidazol-1-yl)-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;5-(4-Chlorophenyl)-6-[4-(methylsulfonyl)phenyl]-4-(piperazin-1-yl)-2-(trifluoromethyl)pyrimidine;4,5-Diphenyl-6-[4-(methylsulfonyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidine;5-(4-Chlorophenyl)-6-[4-(methylsulfonyl)phenyl]-4-(morpholin-1-yl)-2-(trifluoromethyl)pyrimidine;2-Chloro-4-fluoro-5-({4-[6-(4-methylsulfonylphenyl)-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}sulfonyl)benzoicacid;2-Chloro-4-fluoro-5-({4-[6-(4-methylsulfonylphenyl)-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}sulfonyl)benzoicacid sodium salt;4-{4-[(2-Chloro-4-fluorophenyl)sulfonyl]piperazin-1-yl}-6-(4-methylsulfonylphenyl)-5-phenyl-2-(trifluoromethyl)pyrimidine;4-(4-Methylsulfonylphenyl)-5-phenyl-6-[4-chlorophenyl, phenylmethyl))piperazin-1-yl]-2-(trifluoromethyl)pyrimidine; Ethyl4-[5-phenyl-6-(4-methylsulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]piperazine-1-carboxylate;t-Butyl4-[5-phenyl-6-(4-methylsulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]piperazine-1-carboxylate;6-(4-Methylphenyl)-5-phenyl-4-(4-(pyrimidin-2-yl)-piperazin-1-yl)-2-(trifluoromethyl)pyrimidine;6-(4-Fluorophenyl)-5-phenyl-4-(1,3-thiazolidin-3-yl)-2-(trifluoromethyl)pyrimidine;6-(4-Fluorophenyl)-5-phenyl-4-(4-(pyrimidin-2-yl)-piperazin-1-yl-2-(trifluoromethyl)pyrimidine;3-[6-(4-Fluorophenyl)-4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;6-(4-Fluorophenyl)-N-(4-methylpiperazin-1-yl)-5-phenyl-2-(trifluoromethyl)pyrimidin-4-amine;3-[4-(1H-imidazol-1-yl)-5-phenyl-2-(trifluoromethyl)pyrimidin-6-yl]benzenesulfonamide;3-[4-(4-Acetylpiperazin-1-yl)-6-(4-Fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;1-{5-[3-(Aminosulfonyl)phenyl]-6-phenyl-2-(trifluoromethyl)pyrimidin-4-yl}piperidine-4-carboxylicacid;3-[6-(4-Fluorophenyl)-4-(thiomorpholin-4-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;N-({3-[4-(4-Acetylpiperazin-1-yl)-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]phenyl}sulfonyl)acetamide;3-[4-(1-Oxido-1,3-thiazolidin-3-yl)-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-{6-Phenyl-4-[4-(trifluoroacetyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;3-[4-(Cyclopropylamino)-6-(4-methylsulfonylphenyl)-2-(trifluoromethyl)pyrimidin-5-yl]-N-methylbenzenesulfonamide;N-Cyclopropyl-6-(4-fluorophenyl)-5-phenyl-2-(trifluoromethyl)pyrimidin-4-amine;5-Phenyl-6-(4-methylphenyl)-2-(trifluoromethyl)-4-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}pyrimidine;1-[6-(4-Methylphenyl)-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]piperidin-4-one;3-{4-[4-(Hydroxymethyl)piperidin-1-yl]-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;3-[6-Phenyl-4-(4-oxopiperidin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-(4-[4-(2-Furoyl)piperazin-1-yl]-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl)benzenesulfonamide;6-(4-Methylphenyl)-5-phenyl-4-[4-(2-propylpentanoyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidine;N-Cyclopropyl-6-(4-methylphenyl)-5-phenyl-2-(trifluoromethyl)pyrimidin-4-amine;4-[6-(4-Fluorophenyl)-4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;4-[6-(4-Fluorophenyl)-4-(morpholin-4-yl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;3-[4-(2-Methyl-1H-imidazol-1-yl)-6-phenyl-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;4-{5-[3-(Aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}piperazine-1-sulfonylchloride;3-(4-[4-(Cyclopropylcarbonyl)piperazin-1-yl]-6-(4-fluorphenyl)-2-(trifluoromethyl)-pyrimidin-5-yl)benzenesulfonamide;3-[4-(Morpholin-N-yl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]-N-cyclopropylbenzenesulfonamideand6-[4-(Methylsulfonyl)phenyl]-5-phenyl-4-[4-(2-thienylcarbonyl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidine.3. A process for the preparation of compounds of formula (I), wherein, Brepresents pyridine and R represents a halogen atom, according to claim1, by converting the compound of formula (Ia), wherein all the symbolsare as defined earlier, using a halogenating agent in the presence orabsence of a solvent and in the presence or absence ofdimethylformamide, N,N-dimethylaniline or N,N-diethylaniline.


4. A process for the preparation of compounds of formula (I) wherein, Brepresents pyridine and R represents azido or hydrazine or substitutedhydrazine, according to claim 1, by converting the compound of formula(Ib), wherein all the symbols are as defined earlier, in the presence ofone or more equivalents of a metal azide or a hydrazine hydrate orsubstituted hydrazine and a solvent.


5. A process for the preparation of compounds of formula (I) wherein, Rrepresents substituted or unsubstituted heterocyclyl groups, accordingto claim 1, by converting the compound of formula (Ib), wherein all thesymbols are as defined earlier, using appropriate heterocyclyl groups,in the presence or absence of a solvent under acidic or basic or phasetransfer catalysed conditions.
 6. A process for the preparation ofcompounds of formula (I) wherein, R represents —OSO₂R′, according toclaim 1, by converting the compound of formula (Ia), wherein all thesymbols are as defined earlier, using appropriate heterocyclyl or arylor alkyl sulfonyl chlorides or sulfonic acids, in the presence orabsence of a solvent under acidic or basic or phase transfer catalysedconditions.
 7. A process for the preparation of compounds of formula (I)wherein, R₁, R₂, R₃ and R₄ represent SO₂Cl and all other symbols are asdefined earlier, according to claim 1, by converting the compound offormula (Ic), wherein, any of R₁, R₂, R₃ and R₄ represents hydrogen andall other symbols are as defined earlier, using chlorosulfonic acid, inthe presence or absence of a solvent.


8. A process for the preparation of compounds of formula (I), wherein,R₁, R₂, R₃ or R₄ represent —SO₂NHCH₃, —SO₂NHNH₂ and all the othersymbols are as defined earlier, according to claim 1, by converting thecompound of formula (Id), wherein, R₁, R₂, R₃ or R₄ represents —SO₂Cland all the other symbols are as defined earlier, using appropriatealkylamine or hydrazine, in the presence or absence of a solvent.


9. A process for the preparation of compounds of formula (I), wherein, Rrepresents substituted or unsubstituted heteroaryl groups and all theother symbols are as defined earlier, according to claim 1, byconverting the compound of formula (Ie), using reagents such as1-methoxyethylidene malononitrile,ethyl-2-cyano-3,3-bis(methylthio)acrylate, ethoxymethylenemalononitrile, pivaloyl nitrile, acetyl acetone, 1-ethoxyethylidenemalononitrile, in the presence of a solvent.


10. A process for the preparation of compounds of formula (I), wherein,R represents

wherein, R₅ and R₆ represent independently hydrogen, alkyl, halo and allthe other symbols are as defined earlier, according to claim 1, byconverting the compound of formula (Ie), using corresponding cyclicanhydride in the presence of a solvent.
 11. A pharmaceutical compositioncomprising a compound of formula (I), according to claim 1, as an activeingredient, along with a pharmaceutically acceptable carrier, diluent,excipient or solvate.
 12. A pharmaceutical composition according toclaim 11, wherein the composition is in the form of a tablet, capsule,powder, syrup, solution, aerosol or suspension.
 13. A method oftreatment of a pain disorder, inflammation, and immunological diseasesin a mammal comprising administering an effective amount of a compoundaccording to claim 1, to the mammal in need thereof.
 14. (canceled) 15.A method of treatment of rheumatoid arthritis; osteoporosis; multiplemyeloma; uveititis; acute and chronic myelogenous leukemia; ischemicheart disease; atherosclerosis; cancer; ischemic-induced cell damage;pancreatic beta cell destruction; osteoarthritis; rheumatoidspondylitis; gouty arthritis; inflammatory bowel disease; ARDS;psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis;anaphylaxis; contact dermatitis; muscle degeneration; cachexia; asthma;COPD; bone resorption diseases; ischemia reperfusion injury; braintrauma; multiple sclerosis; sepsis; septic shock; toxic shock syndrome;fever and myalgias due to infection in a mammal comprising administeringan effective amount of a compound according to claim 1, to the mammal inneed thereof.
 16. A method of lowering plasma concentrations of anyoneor a combination or all of TNF-α, IL-1β, and IL-6 comprisingadministering an effective amount of a compound according to claim 1, tothe mammal in need thereof.
 17. A method for inhibiting production ofcytokines as selected from TNF-α, IL-1β, and IL-6, IL-12 by the methodcomprising administering the compound of the formula (I) as claimed inclaim
 1. 18. A method of treating immunological diseases, those mediatedby cytokines such as TNF-α, IL-1β, and IL-6, IL-12 comprisingadministering an effective amount of a compound according to claim 1, tothe mammal in need thereof.
 19. A method of treating inflammatorydiseases mediated by PDE4 inhibitors comprising administering aneffective amount of a compound according to claim 1, to the mammal inneed thereof.